Substituted hydroxyethyl amine compounds as beta-secretase modulators and methods of use

ABSTRACT

The present invention comprises a new class of compounds useful for the modulation of Beta-secretase enzyme activity and for the treatment of Beta-secretase mediated diseases, including Alzheimer&#39;s disease (AD) and related conditions. In one embodiment, the compounds have a general Formula I 
                         
or Formula II
 
                         
wherein R 1a , R 1b , R 1c , B, R 3 , R 4 , R 5  and W of Formula I, and R 1a , R 1b , R 1c , R 2 , R 2a , R 3 , R 4 , R 5 , A 1 , A 2 , A 3 , A 4 , W, X, Z, m and n of Formula II are defined herein. The invention also provides compounds of Formula III, sub-Formulas II-A-II-D, sub-Formulas III-A-III-D and Formula IV. The invention further includes use of these compounds in pharmaceutical compositions for treatment, prophylactic or therapeutic, of disorders and conditions related to the activity of beta-secretase protein. Such disorders include, for example, AD, cognitive deficits and impairment, schizophrenia and other similar central nervous system conditions. The invention also comprises further embodiments of Formulas I, II, III, IV and sub-formulas thereof, intermediates and processes useful for the preparation of compounds of Formulas I, II, III, IV and sub-formulas thereof.

This application claims the benefit of U.S. Provisional Application No.60/931,702, filed 25 May 2007, and U.S. Provisional Application No.61/127,022, filed 8 May 2008, which specifications are herebyincorporated here in by reference in their entireties.

FIELD OF THE INVENTION

The invention relates generally to pharmaceutically active compounds,pharmaceutical compositions and methods of use thereof, to treatBeta-Secretase mediated diseases and conditions, including, withoutlimitation, Alzheimer's disease, plaque formation on the brain andrelated disorders.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) affects greater than 12 million aging peopleworldwide. AD accounts for the majority of dementia clinically diagnosedafter the age of 60. AD is generally characterized by the progressivedecline of memory, reasoning, judgement and orientation. As the diseaseprogresses, motor, sensory, and vocal abilities are affected until thereis global impairment of multiple cognitive functions. The loss ofcognitive function occurs gradually, typically leading to a diminishedcognition of self, family and friends. Patients with severe cognitiveimpairment and/or diagnosed as end-stage AD are generally bedridden,incontinent, and dependent on custodial care. The AD patient eventuallydies in about nine to ten years, on average, after initial diagnosis.Due to the incapacitating, generally humiliating and ultimately fataleffects of AD, there is a need to effectively treat AD upon diagnosis.

AD is characterized by two major physiological changes in the brain. Thefirst change, beta amyloid plaque formation, supports the “amyloidcascade hypothesis” which conveys the thought that AD is caused by theformation of characteristic beta amyloid peptide (A-beta), or A-betafragments thereof, deposits in the brain (commonly referred to as betaamyloid “plaques” or “plaque deposits”) and in cerebral blood vessels(beta amyloid angiopathy). The second change in AD is the formation ofintraneuronal tangles, consisting of an aggregate form of the proteintau. Amyloid plaques are thought to be specific for AD, whileintraneuronal tangles are also found in other dementia-inducingdisorders. Joachim et al., Alz. Dis. Assoc. Dis., 6:7-34 (1992).

Several lines of evidence indicate that progressive cerebral depositionof A-beta plays a seminal role in the pathogenisis of AD and can precedecognitive symptoms by years or even decades. Selkoe, Neuron, 6:487(1991). Release of A-beta from neuronal cells grown in culture and thepresence of A-beta in cerebrospinal fluid (CSF) of both normalindividuals and AD patients has been demonstrated. Seubert et al.,Nature, 359:325-327 (1992). Autopsies of AD patients have revealed largenumbers of lesions comprising these 2 factors in areas of the humanbrain believed to be important for memory and cognition.

Smaller numbers of these lesions in a more restricted anatomicaldistribution are found in the brains of most aged humans who do not haveclinical AD. Amyloid containing plaques and vascular amyloid angiopathywere also found in the brains of individuals with Down's Syndrome,Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-type(HCHWA-D), and other neurodegenerative disorders.

It has been hypothesized that A-beta formation is a causative precursoror factor in the development of AD. More specifically, deposition ofA-beta in areas of the brain responsible for cognitive factors isbelieved to be a major factor in the development of AD. Beta amyloidplaques are primarily composed of amyloid beta peptide (A-beta peptide).A-beta peptide is derived from the proteolytic cleavage of a largetransmembrane amyloid precursor protein (APP), and is a peptide rangingin about 39-42 amino acid residues. A-beta 42 (42 amino acids long) isthought to be the major component of these plaque deposits. Citron,Trends in Pharmacological Sciences, 25(2):92-97 (2004).

Several aspartyl proteases are thought to be involved in the processingor cleavage of APP, resulting in the formation of A-beta peptide. Betasecretase (BACE, also commonly referred to as memapsin) is thought tofirst cleave APP to generate two fragments: (1) a first N-terminusfragment (beta APP) and (2) a second C-99 fragment, which issubsequently cleaved by gamma secretase to generate the A-beta peptide.APP has also found to be cleaved by alpha-secretase to producealpha-sAPP, a secreted form of APP that does not result in beta-amyloidplaque formation. This alternate pathway precludes the formation ofA-beta peptide. A decription of the proteolytic processing fragments ofAPP is found, for example, in U.S. Pat. Nos. 5,441,870, 5,712,130 and5,942,400.

BACE is an aspartyl protease enzyme comprising 501 amino acids andresponsible for processing APP at the beta-secretase specific cleavagesite. BACE is present in two forms, BACE 1 and BACE 2, designated assuch depending upon the specific cleavage site of APP. Beta secretase isdescribed in Sinha et al., Nature, 402:537-554 (1999) (p510) and PCTapplication WO 2000/17369. It has been proposed that A-beta peptideaccumulates as a result of APP processing by BACE. Moreover, in vivoprocessing of APP at the beta secretase cleavage site is thought to be arate-limiting step in A-beta production. Sabbagh, M. et al., Alz. Dis.Rev. 3:1-19 (1997). Thus, inhibition of the BACE enzyme activity isdesirable for the treatment of AD.

Studies have shown that the inhibition of BACE may be linked to thetreatment of AD. BACE1 knockout mice have failed to produce A-beta. Whencrossed with transgenic mice that over express APP, the progeny showreduced amounts of A-beta in brain extracts as compares with controlanimals (Luo et al., Nature Neuroscience, 4:231-232 (2001)). Thisevidence further supports the concept that inhibition of beta secretaseactivity and a corresponding reduction of A-beta in the brain shouldprovide a therapeutic method for treating AD and other beta amyloid orplaque related disorders.

Several approaches have been taken to potentially treat AD andplaque-related disorders. One approach has been to attempt to reduce theformation of plaque on the brain, by inhibiting or reducing the activityof BACE. For example, each of the following PCT publications: WO03/045913, WO 04/043916, WO 03/002122, WO 03/006021, WO 03/002518, WO04/024081, WO 03/040096, WO 04/050619, WO 04/080376, WO 04/099376, WO05/004802, WO 04/080459, WO 04/062625, WO 04/042910, WO 05/004803, WO05/005374, WO 03/106405, WO 03/062209, WO 03/030886, WO 02/002505, WO01/070671, WO 03/057721, WO 03/006013, WO 03/037325, WO 04/094384, WO04/094413, WO 03/006423, WO 03/050073, WO 03/029169 and WO 04/000821,describe inhibitors of BACE, useful for treating AD and otherbeta-secretase mediated disorders.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a new class of compounds useful for themodulation of beta secretase activity. To that end, the compounds of theinvention are useful for the regulation or reduction of the formation ofA-beta peptide and, consequently, the regulation and/or reduction ofbeta amyloid plaque formation on the brain. Accordingly, the compoundsare useful for the treatment of Alzheimer's disease and other betasecretase and/or plaque mediated disorders. For example, the compoundsare useful for the prophylaxis and/or treatment, acute and/or chronic,of AD and other diseases or conditions involving the deposition oraccumulation of beta amyloid peptide, and formation of plaque, on thebrain.

The compounds provided by the invention, including stereoisomers,tautomers, solvates, pharmaceutically acceptable salts, derivatives orprodrugs thereof, are generally defined by Formula I

wherein R^(1a), R^(1b), R^(1c), W, B, R³, R⁴ and R⁵, are described belowspecific for Formula I, and of Formula II,

wherein R^(1a), R^(1b), R^(1c), W, R², R^(2a), R³, R⁴, R⁵, X, Z and mare also described below specific for Formula II. The invention alsoprovides procedures for making compounds of Formula I, II, III andsub-Formulas, as well as intermediates useful in such procedures.

The invention further provides pharmaceutical compositions, whichcomprise one or more compounds of the invention, methods for thetreatment of beta secretase mediated diseases, such as AD, using thecompounds and compositions of the invention. For example, and in oneembodiment, the invention provides a pharmaceutical compositioncomprising an effective dosage amount of a compound of Formula I inassociation with at least one pharmaceutically acceptable excipient.

The foregoing merely summarizes certain aspects of the invention and isnot intended, nor should it be construed, as limiting the invention inany way. All patents and other publications recited herein are herebyincorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the invention, the compounds, includingstereoisomers, tautomers, solvates, pharmaceutically acceptable salts,derivatives or prodrugs thereof, are generally defined by

wherein R^(1a) is H, halo, C₁₋₁₀-alkyl, C₂₋₈-alkenyl or C₂₋₈-alkynyl,wherein 1, 2 or 3 carbon atoms of said C₁-C₁₀alkyl, C₂-C₈-alkenyl orC₂-C₈-alkynyl is optionally replaced with a heteroatom selected from O,S, S(O), S(O)₂ and N, and optionally substituted independently with oneor more substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyland the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 3, 4-, 5- or6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷;

R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂;

W is —C(═O)—, —OC(═O)—, —NHC(═O)—, —S(═O)_(b)— or —NHS(═O)_(b)—, whereinb is 1 or 2;

B is R² (CR^(2a)R^(2a))_(h), wherein

-   -   R² is a partially or fully saturated or unsaturated 3-8 membered        monocyclic or 6-12 membered bicyclic, said ring system formed of        carbon atoms optionally including 1-3 heteroatoms if monocyclic        or 1-6 heteroatoms if bicyclic, said heteroatoms selected from        O, N, or S, wherein said ring system is optionally substituted        independently with one or more substituents of oxo, R⁷, NR⁷R⁷,        OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)NR⁷R⁷, NR⁷C(O)R⁷,        NR⁷C(O)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷        or NR⁷S(O)₂R⁷;    -   each R^(2a), independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀        alkyl, C₁-C₁₀ alkoxyl or haloalkyl; and    -   h is 0, 1, 2 or 3;

each R³, independently, is H, haloalkyl, CN, C₁₋₆-alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, each of theC₁₋₆-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl andC₄₋₈-cycloalkenyl optionally comprising 1-2 heteroatoms selected from N,O and S and optionally substituted with 1-5 substituents of R⁷;

R⁴ is H, haloalkyl, CN, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynyl orC₁₋₆-cycloalkyl, wherein each of the C₁₋₆-alkyl, C₁₋₆-alkenyl,C₁₋₆-alkynyl and C₁₋₆-cycloalkyl is optionally substituted with 1-5substitutions of R⁷;

R⁵ is

wherein X¹ is CR⁸R⁸, C(═O), O, S, S(O)₂ or NR⁸;

each X², independently, is CR⁸R⁸;

-   -   each of Y¹, Y² and Y³, independently, is CR⁸R⁸, O, S or NR⁸;    -   Z² taken together with the carbon atoms to which it is attached        is a partially or fully unsaturated 5-6 membered monocyclic        ring, said ring formed of carbon atoms optionally including 1-3        heteroatoms selected from O, N and S;    -   m is 0, 1 or 2;    -   o is 0, 1, 2, 3, 4 or 5; and    -   p is 0, 1, 2, 3, 4 or 5

provided that (a) no more than two of Y¹, Y² and Y³ is O, S or NR⁸ and(b) when o is 0, then each of Y¹ and Y² is CR⁸R⁸;

each R⁷, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl;

each R⁸, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R⁹; and

R⁹ is halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, benzyl, phenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl or a partially or fully saturated or unsaturated 3-6membered monocyclic formed of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl,provided the compound is not

n is 0, 1 or 2, provided the compound is not

-   N-((2S,3R)-4-((S)-6-ethyl-2,2′-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-(4-phenyl-phenyl)-butan-2-yl)acetamide;-   (3S)—N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-1-cyclobutyl-5-oxo-3-pyrrolidinecarboxamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)propanamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2-((cyclopropylmethyl)oxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((2S,4S)-6-ethyl-3,4,4′,5′-tetrahydrospiro[chromene-2,3′-furan]-4-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;-   N′-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-N,N-dimethylbutanediamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2-(methyloxy)acetamide;-   N-((1S,2R)-1-((3-cyano-5-fluorophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)acetamide;-   2-(((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)amino)-2-oxoethyl    dimethylcarbamate;-   N-((1S,2R)-3-(((4S)-8-bromo-6-chloro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide;-   N-1-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)-N˜2-,N˜2˜-dimethylglycinamide;-   Methyl    (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N-dimethylglycyl)amino)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   Methyl    (4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   Methyl    (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3-(((methyloxy)acetyl)amino)butyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;    and-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—(CR^(2a)R^(2a))_(h)— wherein R² is a partially or fullysaturated or unsaturated 3-8 membered monocyclic or 6-12 memberedbicyclic, said ring system formed of carbon atoms optionally including1-3 heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S and said ring system optionallysubstituted independently with one or more substituents of oxo, R⁷,NR⁷R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷ orNR⁷S(O)₂R⁷, each R^(2a), independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀alkyl, C₁-C₁₀ alkoxyl or haloalkyl, and h is 1, 2 or 3, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—(CR^(2a)R^(2a))_(h)— wherein R² is phenyl, naphthyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl, pyranyl, dioxozinyl, benzodioxolyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, each ofis optionally substituted independently with one or more substituents ofoxo, R⁷, NR⁷R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷, COOR⁷, C(O)NR⁷R⁷, NR⁷C(O)R⁷,NR⁷C(O)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷, S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷ orNR⁷S(O)₂R⁷, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—(CH₂)— wherein R² is phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, naphthyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, indolyl,isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,tetrahydrofuranyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,benzodioxolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl orcycloheptyl, each of is optionally substituted independently with achemical moiety which reduces CYP enzyme acitivity and optionally withone or more substituents of oxo, R⁷, NR⁷R⁷, OR⁷, SR⁷, C(O)R⁷, OC(O)R⁷,COOR⁷, C(O)NR⁷R⁷, NR⁷C(O)R⁷, NR⁷C(O)NR⁷R⁷, NR⁷(COOR⁷), OC(O)NR⁷R⁷,S(O)₂NR⁷R⁷, NR⁷S(O)₂NR⁷R⁷ or NR⁷S(O)₂R⁷, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein one R^(2a) is H and the other R^(2a) is OH, NO₂, CN, NH₂, C₁-C₁₀alkyl, C₁-C₁₀ alkoxyl or haloalkyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each R^(2a), independently, is H, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein h is 1, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein h is 2, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—O—(CR^(2a)R^(2a))_(h)— and each R^(2a), independently,is H, OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—(CR^(2a)R^(2a))_(h)— and each R^(2a), independently, isH, OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl or haloalkyl, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—NR^(2a)—(CR^(2a)R^(2a))_(h)— and each R^(2a),independently, is H, OH, NO₂, CN, NH₂, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxyl orhaloalkyl, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—O—(CH₂)_(h)—, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—S—(CH₂)_(h)—, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein B is R²—NH—(CH₂)_(h)—, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R² is an optionally substituted ring selected from phenyl,naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl,quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,benzodioxolyl and benzimidazolyl, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each R³, independently, is H, haloalkyl, CN, C₁₋₆-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, eachof the C₁₋₆-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl andC₄₋₈-cycloalkenyl optionally comprising 1-2 heteroatoms selected from N,O and S and optionally substituted with 1-5 substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl orC₂₋₁₀-alkynyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R³ is H, haloalkyl or C₁₋₁₀-alkyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein each R³, independently, is H, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is H, haloalkyl, CN, C₁₋₆-alkyl, C₁₋₆-alkenyl, C₁₋₆-alkynylor C₁₋₆-cycloalkyl, wherein each of the C₁₋₆-alkyl, C₁₋₆-alkenyl,C₁₋₆-alkynyl and C₁₋₆-cycloalkyl is optionally substituted with 1-5substitutions of R⁷, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is H, haloalkyl, CN or C₁₋₆-alkyl, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁴ is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is

wherein X¹ is CR⁸R⁸, C(═O), O, S, S(O)₂ or NR⁸;

each X², independently, is CR⁸R⁸;

-   -   each of Y¹, Y² and Y³, independently, is CR⁸R⁸, O, S or NR⁸;    -   Z² taken together with the carbon atoms to which it is attached        is a partially or fully unsaturated 5-6 membered monocyclic        ring, said ring formed of carbon atoms optionally including 1-3        heteroatoms selected from O, N and S;    -   m is 0, 1 or 2;    -   o is 0, 1, 2, 3, 4 or 5; and    -   p is 0, 1, 2, 3, 4 or 5

provided that (a) no more than two of Y¹, Y² and Y³ is O, S or NR⁸ and(b) when

o is 0, then each of Y¹ and Y² is CR⁸R⁸, in conjunction with any of theabove or below embodiments.

In the immediately preceeding embodiment, the compounds of Formula Iincludes compounds wherein X¹ is CR⁸R⁸, in conjunction with any of theabove or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X¹ is C(═O), in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X¹ is 0, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X¹ is S, in conjunction with any of the above or belowembodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X¹ is S(O)₂, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X¹ is NR⁸, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X² is CR⁸R⁸, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein X² is CH₂, in conjunction with any of the above orbelow embodiments.

In the preceeding embodiment, Formula I includes compounds wherein eachof Y¹, Y² and Y³, independently, is CR⁸R⁸, in conjunction with any ofthe above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein each of Y¹, Y² and Y³, independently, is CR⁸R⁸, O, Sor NR⁸, in conjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein each of Y¹, Y² and Y³, independently, is CHR⁸, inconjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein each of Y¹, Y² and Y³, independently, is CH₂, inconjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein no more than two of Y¹, Y² and Y³, independently, is 0and the remaining of Y¹, Y² and Y³, independently, is CR⁸R⁸, inconjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein one of Y¹, Y² and Y³, independently, is 0 and theother two of Y¹, Y² and Y³, independently, is CR⁸R⁸, in conjunction withany of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein Y² is 0 and Y¹ and Y³, independently, are CR⁸R⁸, inconjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein Y² is S and Y¹ and Y³, independently, are CR⁸R⁸, inconjunction with any of the above or below embodiments.

In the preceeding embodiment, the compounds of Formula I includescompounds wherein Y² is —NR⁸— and Y¹ and Y³, independently, are CR⁸R⁸,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein Z² is an optionally substituted phenyl, pyridine, pyrimidine,triazine, pyridazine, pyrazine, pyridone, pyrrole, imidazole, pyrazole,triazole, thiophene, thiazole, thiadiazole, isothiazole, furan, oxazole,oxadiazole or isoxazole ring, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein Z² is a 5- or 6-membered aromatic ring which is preferablysubstituted with a chemical moiety which reduces CYP enzyme activity, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein Z² is a phenyl, pyridine, pyrimidine, triazine, pyridazine,pyrazine, pyridone, pyrrole, imidazole, pyrazole, triazole, thiophene,thiazole, thiadiazole, isothiazole, furan, oxazole, oxadiazole orisoxazole ring, each of which is preferably substituted with a chemicalmoiety which reduces CYP enzyme activity, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is

wherein each of A¹, A², A³ and A⁴, independently, is CR⁸ or N, providedthat no more than two of A¹, A², A³ and A⁴ is N;

-   -   m, o, R⁸, X², Y¹, Y² and Y³ are as defined herein;    -   X¹ is CR⁸, C(═O), O, S, S(O)₂ or NR⁸; and    -   p is 0, 1, 2 or 3, in conjunction with any of the above or below        embodiments.

In the immediately preceeding embodiment, the compounds of Formula Iincludes compounds wherein each of A¹, A², A³ and A⁴, independently, isCR⁸ or N, provided that no more than one of A¹, A², A³ and A⁴ is N, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula I includes compoundswherein R⁵ is

wherein o is 1 or 2;

p is 0, 1, 2 or 3;

each of A¹, A², A³ and A⁴, independently, is CR⁸ or N, provided that nomore than two of A¹, A², A³ and A⁴ is N;

X¹ is CH, C(═O), O or NR¹²;

Y³ is CR¹² or O ; and

each R⁸, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, Cl₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a ring selected from phenyl,pyridyl, pyrimidinyl, triazinyl, thiophenyl, furyl, tetrahydrofuranyl,pyrrolyl, pyrazolyl, thieno-pyrazolyl, imidazolyl, triazolyl,tetrazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxolyl,dioxazinyl, cyclopropyl, cyclobutyl, azetidinyl, cyclopentyl, cyclohexyland cycloheptyl, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl, in conjunction with any of the above or belowembodiments.

In another embodiment, Formula I includes compounds wherein R^(1a) isC₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl, C₁₋₆alkyl-O—C₁₋₃-alkyl-,C₁₋₆-alkyl-S—C₁₋₃-alkyl-, C₁₋₆-alkyl-S(O)₂—C₁₋₃-alkyl-,C₁₋₆-alkyl-NH—C₁₋₃-alkyl, di-(C₁₋₃-alkyl)-N—C₁₋₃-alkyl,C₂₋₄-alkenyl-O—C₁₋₃-alkyl-, C₂₋₄-alkenyl-S—C₁₋₃-alkyl-,C₂₋₄-alkenyl-NH—C₁₋₃-alkyl- or C₂₋₄-alkynyl-NH—C₁₋₃-alkyl-, wherein thealkyl, alkenyl or alkynyl moiety of each is optionally substituted with1-3 substituents of R⁷;

W is —C(═O)—;

B is R²(CR^(2a)R^(2a))_(h)—, wherein each R², independently, is H orC₁-C₆ alkyl;

-   -   h is 1 or 2; and    -   R² is ring selected from phenyl, naphthyl, pyridyl, pyrimidyl,        pyridazinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl,        quinazolinyl, isoquinazolinyl, phthalazinyl, thiophenyl, furyl,        pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,        thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,        oxadiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl,        benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,        benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl,        pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,        pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl,        dioxozinyl, benzodioxolyl, cyclopropyl, cyclobutyl, cyclopentyl,        cyclohexyl and cycloheptyl, said ring optionally substituted        independently with 1-5 substituents of R⁷;

each R³, independently, is H, haloalkyl, CN, C₁₋₆-alkyl, C₂₋₆-alkenyl orC₂₋₆-alkynyl;

R⁴ is H, CN or C₁₋₁₀-alkyl;

R⁵ is

wherein each of A¹, A², A³ and A⁴, independently, is CR⁸ or N, providedthat no more than one of A¹, A², A³ and A⁴ is N;

-   -   m, o, R⁵, X², Y¹, Y² and Y³ are as defined in claim 1;    -   X¹ is CR⁸, C(═O), O, S, S(O)₂ or NR⁸; and    -   p is 0, 1, 2 or 3;

each R⁷, independently, is H, Cl, F, Br, I, haloalkyl, CN, OH, NO₂, NH₂,acetyl, methyl, methoxyl, ethyl, ethoxyl, allyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl, benzyl or phenyl;

each R⁸, independently, is Cl, F, Br, I, haloalkyl, CN, OH, NO₂, NH₂,acetyl, methyl, methoxyl, ethyl, ethoxyl, allyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, neopentyl, cyclopentyl, hexyl, cyclohexyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl or a ringsystem selected from phenyl, pyridyl, pyrimidinyl, triazinyl,thiophenyl, furyl, tetrahydrofuranyl, pyrrolyl, pyrazolyl,thieno-pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,thiadiazolyl, oxazolyl, oxadiazolyl, oxadiazolyl, isoxazolyl,isothiazolyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrrolidinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl, pyranyl, dioxozinyl,2,3-dihydro-1,4-benzoxazinyl, 1,3-benzodioxolyl and azetidinyl, saidring system optionally substituted independently with 1-3 substituentsof R⁹; and

R⁹ is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₇-cycloalkyl, C₄₋₇-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl,C₁₋₁₀-thioalkoxyl.

Incorporation of a chemical moiety (R³) at specific regions or locationsof compounds of Formula I (including without limitation, on variable Band on variable R⁵ of Formula I), the R³ group of Formulas II, II-A,II-B, II-C, II-D, III-A, III-B, III-C and III-D, and on R² in FormulaIV, have been unexpectedly found to generally modify, and morespecifically improve, the compound's characteristics and properties,particularly as they relate to projected in-vivo properties, includingpharmacokinetic and pharmacodynamic properties. In essence, suchmoieties have been surprisingly found to generally improve the abilityof a given compound to be useful in treatment and therapy of AD andother BACE mediated diseases linked to plaque formation and depositionin subjects. It has also been found that compounds where R² group ofFormula I, or the benzyl moiety, optionally substituted with m number ofR² groups, having 2 adjacent R² groups tied together to form a dioxolylgroup has generally improved in-vivo properties. Accordingly, in anotherembodiment, the invention provides compounds of Formula II:

or a pharmaceutically acceptable salt thereof, wherein

each of A¹, A¹, A² and A⁴, independently, is N, CH or CR⁶, provided thatno more than two of A¹, A², A³ and A⁴ is N;

R^(1a) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkylportion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted independently with 1-5substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkylportion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted independently with 1-5substituents of R⁷;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 3-, 4-, 5-or 6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷;

R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂;

W is —C(═O)—, —C(═S)—, —OC(═O)—, —NHC(═O)—, —S(═O)_(b)— or—NHS(═O)_(b)—, wherein b is 1 or 2;

each R², independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH, NH₂,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo;

R^(2a) is H or F;

R³ is CN, C₂₋₃alkynyl, a partially or fully unsaturated 5- or 6-memberedmonocyclic ring formed of carbon atoms wherein said ring optionallyincluding 1-3 heteroatoms selected from O, N, or S and optionallysubstituted with 1-5 substituents of R⁷, or R³ is F or absent when twoadjacent R² groups taken together with the carbon atoms to which theyare attached form a dioxolyl ring;

R⁴ is H, halo or C₁₋₆-alkyl;

R⁵ is H, halo, haloalkyl, oxo, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyland the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷;

X is CH₂, CHR⁶, CR⁶R⁶, C(═O), O, NH, NR⁶ or S(O)_(o) wherein o is 0, 1or 2;

Z is a 3-6 membered spirocyclic ring formed of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N and S and optionallysubstituted independently with 1-5 substituents of R⁷;

each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

or R⁶ is a fully saturated or partially or fully unsaturated 5- or6-membered monocyclic or bicyclic ring formed of carbon atoms, said ringoptionally including 1-4 heteroatoms selected from O, N, or S andoptionally substituted with one or more substituents of R⁷

each R⁷, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fully saturated or partially orfully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic,said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; and

m is 0, 1, 2 or 3, provided the compound of Formula II is not

-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2-((cyclopropylmethyl)oxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;-   N′-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-N,N-dimethylbutanediamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2-(methyloxy)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)acetamide;-   2-(((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)amino)-2-oxoethyl    dimethylcarbamate;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)acetamide;-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide;-   N˜1˜-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)-N˜2˜,N˜2˜-dimethylglycinamide;-   methyl    (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N-dimethylglycyl)amino)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   methyl    (4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   methyl    (4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3-(((methyloxy)acetyl)amino)butyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;    and-   N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide.

Thus, the specific compounds listed above are excluded from the scope ofthe present invention and from the scope of Formulas I and II describedherein.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is H, halo, C₁₋₁₀-alkyl, C₂₋₈-alkenyl orC₂₋₈-alkynyl, wherein 1, 2 or 3 carbon atoms of said C₁-C₁₀alkyl,C₂-C₈-alkenyl or C₂-C₈-alkynyl is optionally replaced with a heteroatomselected from O, S, S(O), S(O)₂ and N, and optionally substitutedindependently with one or more substituents of R⁷, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is H, halo, C₁₋₁₀-alkyl, C₂₋₈-alkenyl orC₂₋₈-alkynyl, wherein 1, 2 or 3 carbon atoms of said C₁-C₁₀alkyl,C₂-C₈-alkenyl or C₂-C₈-alkynyl is optionally replaced with a heteroatomselected from O, S, S(O), S(O)₂ and N, and optionally substitutedindependently with 1-3 substituents of halo, haloalkyl, CN, OH, NO₂,NH₂, acetyl, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl,C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl and C₁₋₁₀-thioalkoxyl, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,—O—C₁₋₆-alkyl-, —S—C₁₋₆-alkyl-, —NH—C₁₋₆-alkyl-, —O—C₁₋₆-alkenyl-,—S—C₂₋₆-alkenyl-, —NH—C₂₋₆-alkenyl-, —O—C₁₋₆-alkynyl-, —S—C₁₋₆alkynyl-,—NH—C₁₋₆-alkynyl-, —C₁₋₄alkyl-O—C₁₋₄-alkyl-, —C₁₋₄-alkyl-S—C₁₋₄-alkyl-or —C₁₋₄-alkyl-NH—C₁₋₄-alkyl-, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OHor NH₂, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl areoptionally substituted independently with 1-5 substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl and —NH—C₁₋₆-alkyl is optionallysubstituted independently with 1-5 substituents of R⁷, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OHor NH₂, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl areoptionally substituted independently with 1-5 substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OHor NH₂, wherein the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OHor NH₂, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1b) is H, F, Cl, Br, CF₃, C₂F₅, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl andthe C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl and—NH—C₁₋₆-alkyl is optionally substituted independently with 1-3substituents of R⁷, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein each of R^(1a) and R^(1b), independently, is H,methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, eachof which is optionally substituted independently with 1-3 substituentsof halo, OH, NH₂ and CN, and provided that both of R^(1a) and R^(1b) arenot H, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a partially or fully saturated 3, 4-, 5-or 6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a partially or fully saturated 4-, 5- or6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a ring selected fromtetrahydrofuran-2-yl, tetrahydrofuran-3-yl, morpholin-2-yl, cyclopropyl,cyclobutyl and cyclohexyl, the ring optionally substituted independentlywith 1-3 substituents of R⁷, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OHor NH₂, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl, CN, OH orNH₂, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) is C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,—O—C₁₋₆-alkyl-, —S—C₁₋₆-alkyl-, —NH—C₁₋₆-alkyl-, —O—C₁₋₆-alkenyl-,—S—C₂₋₆-alkenyl-, —NH—C₂₋₆-alkenyl-, —O—C₁₋₆-alkynyl-, —S—C₁₋₆alkynyl-,—NH—C₁₋₆-alkynyl-, —C₁₋₄alkyl-O—C₁₋₄-alkyl-, —C₁₋₄-alkyl-S—C₁₋₄-alkyl-or —C₁₋₄-alkyl-NH—C₁₋₄-alkyl-;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂; and

R^(1c) is H, in conjunction with any of the above or below embodiments.In another embodiment, the compounds of Formulas I and II includecompounds wherein each of R^(1a) and R^(1b), independently, is H,methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, eachof which is optionally substituted independently with 1-3 substituentsof halo, OH, NH₂ and CN, and provided that both of R^(1a) and R^(1b) arenot H,

-   and R^(1c) is H, in conjunction with any of the above or below    embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a partially or fully saturated 3, 4-, 5-or 6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷ and R^(1c) is H, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a partially or fully saturated 4-, 5- or6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷ and R^(1c) is H, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein R^(1a) and R^(1b) taken together with the carbon atomto which they are attached form a ring selected fromtetrahydrofuran-2-yl, tetrahydrofuran-3-yl, cyclopropyl, cyclobutyl andcyclohexyl, the ring optionally substituted independently with 1-3substituents of R⁷ and R^(1c) is H, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein each of R^(1a) and R^(1b), independently, is H,methyl, ethyl, propyl, butyl, methoxyl, ethoxyl, propoxyl, butoxyl, eachof which is optionally substituted independently with 1-3 substituentsof halo, OH, NH₂ and CN, and provided that both of R^(1a) and R^(1b) arenot H, and R^(1c) is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —C(═O)—, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —OC(═O)—, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —NHC(═O)—, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —S(═O)_(b)— wherein b is 1 or 2, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —NHS(═O)_(b)— wherein b is 1 or 2, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —C(═O)—, —C(═S)—, —OC(═O)—, —NHC(═O)—,—S(═O)_(b)— or —NHS(═O)_(b)—, wherein b is 1 or 2, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formulas I and II includecompounds wherein W is —C(═O)—, —C(═S)— or —S(═O)_(b)—, wherein b is 1or 2, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein each of A, A¹, A² and A⁴, independently, is N, CH or CR⁶,provided that no more than two of A¹, A², A³ and A⁴ is N, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein each of A¹ and A², independently, is CH and one of A³ and A⁴,independently, is N while the other of A³ and A⁴, independently, is CHor CR⁶, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶ and one of A³ and A⁴, independently, is Nwhile the other of A³ and A⁴, independently, is CH or CR⁶, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶, A³ is N and A⁴ is CH or CR⁶, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶, A³ is CH or CR⁶ and A⁴ is N, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶ and each of A³ and A⁴, independently, CH,CR⁶ or N, provided no more than one of A³ and A⁴ is N, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶ and each of A³ and A⁴, independently, CH orCR⁶, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein A¹ is CH, A² is CR⁶, A³ is CH and A⁴ is CR⁶, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formulas II includes compoundswherein each R², independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH,NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R², independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH,NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R², independently, is F, Cl, Br, CF₃, C₂F₅, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH,NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₈-cycloalkyl, wherein theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl and theC₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted with 1-3 substituents of R⁷,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein two adjacent R² groups taken together with the carbon atoms towhich they are attached form a dioxolyl ring optionally substituted by 1or 2 halo, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R², is H or F, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R², is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R^(2a) is F, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is CN, C₂₋₃alkynyl, a partially or fully unsaturated 5- or6-membered monocyclic ring formed of carbon atoms wherein said ringoptionally including 1-3 heteroatoms selected from O, N, or S andoptionally substituted with 1-5 substituents of R⁷, or R³ is F or absentwhen two adjacent R² groups taken together with the carbon atoms towhich they are attached form a dioxolyl ring, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is CN, C₂₋₃alkynyl, a partially or fully unsaturated 5- or6-membered monocyclic ring formed of carbon atoms wherein said ringoptionally including 1-3 heteroatoms selected from O, N, or S andoptionally substituted with 1-5 substituents of R⁷, or R³ is absent whentwo adjacent R² groups taken together with the carbon atoms to whichthey are attached form a dioxolyl ring, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is C₂₋₃alkynyl or a partially or fully unsaturated 5- or6-membered monocyclic ring formed of carbon atoms wherein said ringoptionally including 1-3 heteroatoms selected from O, N, or S andoptionally substituted with 1-5 substituents of R⁷, or R³ is absent whentwo adjacent R² groups taken together with the carbon atoms to whichthey are attached form a dioxolyl ring, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is C₂₋₃alkynyl or a fully unsaturated 5- or 6-memberedmonocyclic ring formed of carbon atoms wherein said ring optionallyincluding 1-3 heteroatoms selected from O, N, or S and optionallysubstituted with 1-5 substituents of R⁷, or R³ is absent when twoadjacent R² groups taken together with the carbon atoms to which theyare attached form a dioxolyl ring, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl and pyranyl, said ring optionally substitutedwith 1-5 substituents of R⁷, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl and pyranyl, said ring optionally substitutedwith 1-5 substituents of R⁷, or R³ is absent when two adjacent R² groupstaken together with the carbon atoms to which they are attached form adioxolyl ring, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is a ring selected from 1H-imidazol-1-yl, 1H-imidazol-2-yl,1H-imidazol-4-yl, 1H-imidazol-5-yl, 1,3-thiazol-5-yl, 1,3-thiazol-4-yl,1,3-thiazol-2-yl, 4-pyridyl, 3-pyridyl, 2-pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, pyrazolyl, 1,3-oxazol-2-yl, 1,3-oxazol-4-yl,1,3-oxazol-5-yl, isoxazolyl, isothiazolyl, thiadiazolyl and oxadiazolyl,said ring optionally substituted with 1-5 substituents of R⁷, or R³ isabsent when two adjacent R² groups taken together with the carbon atomsto which they are attached form a dioxolyl ring, in conjunction with anyof the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R³ is absent and two adjacent R² groups taken together with thecarbon atoms to which they are attached form a 1,3-dioxolyl ring, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H, halo or C₁₋₆-alkyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H, halo or C₁₋₄-alkyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H or C₁₋₆-alkyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H, F or methyl, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H or methyl, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁴ is H, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁵ is H, halo, haloalkyl, oxo, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, whereinthe C₁₋₆-alkyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted independently with 1-5 substituents of R⁷, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁵ is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁵ is H, F, Cl, Br, CF₃, C₂F₅, CH₂CF₃, methyl, ethyl, methoxyl,ethoxyl, CN, OH or NH₂, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷,NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

or R⁶ is a fully saturated or partially or fully unsaturated 5- or6-membered monocyclic or bicyclic ring formed of carbon atoms, said ringoptionally including 1-4 heteroatoms selected from O, N, or S andoptionally substituted with one or more substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷,NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein R⁶ is a fully saturated or partially or fully unsaturated 5- or6-membered monocyclic or bicyclic ring formed of carbon atoms, said ringoptionally including 1-4 heteroatoms selected from O, N, or S andoptionally substituted with one or more substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷,NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl ora ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl andpyranyl, wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, ring and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl areoptionally substituted with 1-5 substituents of R⁷, in conjunction withany of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷,NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CH₂, CHR⁶, CR⁶R⁶, C(═O), O, NH, NR⁶, or S(O)_(o) wherein ois 0, 1 or 2, in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CH₂, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CHR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CR⁶R⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is C(═O), in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is O, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is NH, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is NR⁶, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is S(O)_(o) wherein o is 0, 1 or 2, in conjunction with any ofthe above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CH₂, CHR⁶, O, NH, NR⁶, or S(O)_(o) wherein o is 0, 1 or 2,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is CH₂, C(═O), O, NH, NR⁶, or S(O)_(o) wherein o is 0, 1 or 2,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is C(═O), O, NH, NR⁶, or S(O)_(o) wherein o is 0, 1 or 2, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is O, NH, NR⁶, or S(O)_(o) wherein o is 0, 1 or 2, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein X is O, NH or NR⁶ in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein Z is a 3-6 membered spirocyclic ring formed of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S andoptionally substituted independently with 1-5 substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein Z is a cyclopropyl, cyclobutyl or cyclopentyl ring wherein 0, 1or 2 carbon atoms of the ring are, independently, replaced with anoxygen atom and the ring optionally substituted independently with 1-5substituents of R⁷, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II includes compoundswherein Z is a ring of

wherein R⁷ is as defined herein and p is 0, 1, 2, 3 or 4, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundswherein Z is a 3-6 membered spirocyclic ring formed of carbon atomsoptionally including 1-3 heteroatoms selected from O, N and S andoptionally substituted independently with 1-5 substituents of R⁷, inconjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula II includes compoundsand pharmaceutically acceptable salt forms thereof, wherein

A¹ is CH;

A² is CR⁶;

each of A³ and A⁴, independently, CH, CR⁶ or N, provided no more thanone of A³ and A⁴ is N;

R^(1a) is C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₁₋₆alkyl-O—C₁₋₃-alkyl-, C₁₋₆-alkyl-S—C₁₋₃-alkyl-,C₁₋₆-alkyl-S(O)₂—C₁₋₃-alkyl-, C₁₋₆-alkyl-NH—C₁₋₃-alkyl,di-(C₁₋₃-alkyl)-N—C₁₋₃-alkyl, C₂₋₄-alkenyl-O—C₁₋₃-alkyl-,C₂₋₄-alkenyl-S—C₁₋₃-alkyl-, C₂₋₄-alkenyl-NH—C₁₋₃-alkyl- orC₂₋₄-alkynyl-NH—C₁₋₃-alkyl-, wherein the alkyl, alkenyl or alkynylmoiety of each is optionally substituted with 1-3 substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 5- or6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷;

R^(1c) is H;

W is —C(═O)—;

each R², independently, is halo, haloalkyl, C₁₋₄-alkyl, —O—C₁₋₄-alkyl,—S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, —N-di-C₁₋₄-alkyl, CN, OH, NH₂,C₂₋₄-alkenyl, C₂₋₄-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo;

R^(2a), is H;

R³ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl and pyranyl, said ring optionally substituted with 1-5substituents of R⁷, or R³ is absent when two adjacent R² groups takentogether with the carbon atoms to which they are attached form adioxolyl ring;

R⁴ is H or C₁₋₄-alkyl;

R⁵ is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂;

X is CH², CHR⁶, C(═O) or O;

Z is a cyclopropyl, cyclobutyl or cyclopentyl ring wherein 0, 1 or 2carbon atoms of the ring are, independently, replaced with an oxygenatom and the ring optionally substituted independently with 1-5substituents of R⁷; and

each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl or a ringselected from phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl,thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl, piperazinyl andpyranyl, wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, ring and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl areoptionally substituted with 1-5 substituents of R⁷.

In another embodiment, the invention provides compounds, andpharmaceutically acceptable salt forms thereof, having a general FormulaII-A:

wherein

each of A³ and A⁴, independently, CH, CR⁶ or N, provided no more thanone of A³ and A⁴ is N;

R^(1a) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyland the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyland the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 4-, 5- or6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷;

R^(1c) is H, F, Cl, methyl, ethyl, methoxyl, ethyoxyl, CN, OH or NH₂;

each R², independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH, NH₂,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo;

R^(2a) is H or F;

R³ is CN, C₂₋₃alkynyl or a ring selected from imidazolyl, thiazolyl,pyridyl, pyazolyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl,thiophenyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl,isothiazolyl, thiadiazolyl or oxadiazolyl, said ring optionallyincluding 1-3 heteroatoms selected from O, N, or S and optionallysubstituted with 1-3 substituents of R⁷;

R⁴ is H, halo or C₁₋₄-alkyl;

R⁵ is H, halo, haloalkyl, C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl,—NH—C₁₋₄-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyl and the C₁₋₄-alkylportion of —O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl and —N—C₁₋₄-alkyl are optionallysubstituted independently with 1-3 substituents of R⁷;

each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

each R⁷, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fully saturated or partially orfully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic,said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl;

m is 0, 1, 2 or 3;

n is 0, 1 or 2; and

p is 0, 1 or 2.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 0, 1, 2 or 3, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 0, 1 or 2, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 0 or 1, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 1 or 2, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 1, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein m is 0, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein n is 0, 1 or 2, in conjunction with any of the aboveor below embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein n is 0 or 1, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein n is 1, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula II and II-A includecompounds wherein n is 0, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of II-A include compounds whereinR^(1a) is C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl and —NH—C₁₋₆-alkyl is optionally substituted independentlywith 1-5 substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl and —NH—C₁₋₆-alkyl is optionallysubstituted independently with 1-5 substituents of R⁷;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 4- or5-membered ring of carbon atoms optionally including 1 or 2 oxygen atomsand optionally substituted independently with 1-3 substituents of R⁷;and

R^(1c) is H, F, Cl, methyl or ethyl, in conjunction with any of theabove or below embodiments.

In another embodiment, the compounds of Formula II-A includes compoundswherein each of the specific embodiments for A³, A⁴, R^(1a), R^(1b),R^(1c), R², R^(2a), R³, R⁴, R⁵, R⁶, m, n and p, respectively, ofcompounds of Formula II above apply for compounds of Formula II-A.

In another embodiment, the invention provides compounds, andpharmaceutically acceptable salt forms thereof, having a general FormulaII-B:

wherein each of the independent embodiments for A³, A⁴, R^(1a), R^(1b),R^(1c), R², R^(2a), R³, R⁴, R⁵, R⁶, R⁷, m, n and p, respectively, ofcompounds of Formulas II and II-A apply for compounds of Formula II-B.

In another embodiment, the invention provides compounds of Formula II-C:

or a pharmaceutically acceptable salt thereof, wherein

each of A¹, A², A³ and A⁴, independently, is N, CH or CR⁶, provided thatno more than one of A¹, A², A³ and A⁴ is N;

R^(1a) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkylportion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted independently with 1-5substituents of R⁷;

R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkylportion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted independently with 1-5substituents of R⁷;

alternatively, R^(1a) and R^(1b) taken together with the carbon atom towhich they are attached form a partially or fully saturated 3-, 4-, 5-or 6-membered ring of carbon atoms optionally including 1-2 heteroatomsselected from O, N, or S, the ring optionally substituted independentlywith 1-3 substituents of R⁷;

R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂;

W is —C(═O)—, —C(═S)—, —OC(═O)—, —NHC(═O)—, —S(═O)_(b)— or—NHS(═O)_(b)—, wherein b is 1 or 2;

each R², independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH, NH₂,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo;

R^(2a), is H or F;

R³ is CN, C₂₋₃alkynyl, a partially or fully unsaturated 5- or 6-memberedmonocyclic ring formed of carbon atoms wherein said ring optionallyincluding 1-3 heteroatoms selected from O, N, or S and optionallysubstituted with 1-5 substituents of

R⁷, or R³ is absent when two adjacent R² groups taken together with thecarbon atoms to which they are attached form a dioxolyl ring;

R⁴ is H, halo or C₁₋₆-alkyl;

R⁵ is H, halo, haloalkyl, oxo, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆alkyl, —N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyland the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionally substitutedindependently with 1-5 substituents of R⁷;

X is CH₂, CHR⁶, CR⁶R⁶, C(═O), O, NH, NR⁶, or S(O)_(o) wherein o is 0, 1or 2;

Z is a 3-6 membered spirocyclic ring formed of carbon atoms optionallyincluding 1-3 heteroatoms selected from O, N and S and optionallysubstituted independently with 1-5 substituents of R⁷;

each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷;

or R⁶ is a fully saturated or partially or fully unsaturated 5- or6-membered monocyclic or bicyclic ring formed of carbon atoms, said ringoptionally including 1-4 heteroatoms selected from O, N, or S andoptionally substituted with one or more substituents of R⁷ each R⁷,independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fully saturated or partially orfully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic,said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; and

m is 0, 1, 2 or 3.

In another embodiment, the invention provides compounds, andpharmaceutically acceptable salt forms thereof, wherein each of theindependent embodiments for Formulas II and II-A apply for compounds ofFormula II-C.

In another embodiment, the invention provides compounds, andpharmaceutically acceptable salt forms thereof, having a general FormulaII-D:

wherein each of A³, A⁴, R^(1a), R^(1b), R^(1c), R², R^(2a), R³, R⁴, R⁵,R⁶, R⁷, m, n and p are defined herein with respect to Formula II, II-Aand II-B above.

In another embodiment, the invention provides the compound of FormulaII, or a pharmaceutically acceptable salt thereof, selected from

-   (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;-   (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-fluoropropanamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-oxetanecarboxamide;-   (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-oxetanecarboxamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2,2-dimethoxyacetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-methoxyacetamide;-   N—((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1H-imidazol-1-yl)benzyl)propyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(4-pyridinyl)benzyl)propyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(4-pyridinyl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-8′-chloro-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-5-yl)benzyl)propyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-4-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-5-yl)benzyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1H-imidazol-1-yl)benzyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-4-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-5-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1H-imidazol-1-yl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-4-yl)benzyl)propyl)-2-methoxyacetamide;-   N-((1R,2S)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)acetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((1    s,3R,4′S)-6′-(2,2-dimethylpropyl)-3-methyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((1s,3S,4′S)-6′-(2,2-dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)propanamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;-   N—((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1-methyl-1H-imidazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2,2-dimethoxyacetamide;-   N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N—((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(5-methyl-1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-((6′-(2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-3-((6′-(2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;-   (2R)—N-((1S,2R)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxypropanamide;-   N-((1S,2R)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4S)-6-(2-methylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2-methoxyacetamide;-   N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-ethoxyacetamide;-   N-((1S,2R)-1-(3-ethynyl-4-fluorobenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   (2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;-   (2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro-2-furancarboxamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro-2-furancarboxamide;-   N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N—((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;-   N-((1S,2R)-3-(((3S,4′S)-6′-(2,2-dimethylpropyl)-3′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;-   N-((1S,2R)-3-(((3S,4′R)-6′-(2,2-dimethylpropyl)-3′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(2-pyridinyl)benzyl)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((3S,4′S)-6′-(2,2-dimethylpropyl)-3′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   N—((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-ethoxyacetamide;-   N-((1S,2R)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2,2-dimethoxyacetamide;-   (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)-2-methoxypropanamide;-   (2R)—N-((1S,2R)-1-(3-ethynylbenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxypropanamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-ethoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-ethoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;-   N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;-   N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxyacetamide;-   (2R)—N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;    and-   N-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-ethoxyacetamide.

In another embodiment, the invention provides compound of Formula III-Agenerally defined by

wherein each of A⁴, R^(1a), R^(1b), R^(1c), R², R^(2a), R³, R⁴, R⁵, R⁶,R⁷, m, n and p are defined herein with respect to Formula II and II-Aabove.

In another embodiment, the invention provides compound of Formula III-Bgenerally defined by

wherein each of A³, R^(1a), R^(1b), R^(1c), R², R^(2a), R³, R⁴, R⁵, R⁶,R⁷, m, n and p are defined herein with respect to Formula II and II-Aabove.

In another embodiment, the invention provides compound of Formula III-Cgenerally defined by

wherein each of A⁴, R^(1a), R^(1b), R^(1c), R²R^(2a), R³, R⁴, R⁵, R⁶R⁷,m, n and p are defined herein with respect to Formula II and II-A above.

In another embodiment, the invention provides compound of Formula III-Dgenerally defined by

where in each of A³, R^(1a), R^(1b), R^(1c), R²R^(2a), R³, R⁴, R⁵, R⁶,R⁷, m, n and p are defined herein with respect to Formula II and II-Aabove.

For example, and in another embodiment, the compounds of Formulas III-Aand B include compounds wherein R³ is CN, C₂₋₃alkynyl, a partially orfully unsaturated 5- or 6-membered monocyclic ring formed of carbonatoms wherein said ring optionally including 1-3 heteroatoms selectedfrom O, N, or S and optionally substituted with 1-5 substituents of R⁷,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formulas III-A and B includecompounds wherein R³ is C₂₋₃alkynyl or a ring selected from phenyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl, saidring optionally substituted with 1-5 substituents of R⁷, in conjunctionwith any of the above or below embodiments.

In another embodiment, the compounds of Formulas III-A and B includecompounds wherein R³ is a ring selected from phenyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,piperidinyl, piperazinyl and pyranyl, said ring optionally substitutedwith 1-5 substituents of R⁷, in conjunction with any of the above orbelow embodiments.

In another embodiment, the present invention includes compoundsgenerally defined by Formula IV:

and stereoisomers, tautomers, solvates, pharmaceutically acceptablesalts, derivatives and prodrugs thereof, wherein

A is C₁₋₆-alkyl, C₂₋₆-alkenyl or C₂₋₆alkynyl, wherein 1, 2 or 3 carbonatoms of said C₁₋₆-alkyl, C₂₋₆-alkenyl and C₂₋₆alkynyl is optionallyreplaced with a heteroatom selected from O, S, S(O), S(O)₂ and NH, andoptionally substituted independently with 1-3 substituents of R⁷;

W is —C(═O)—, —OC(═O)—, —NHC(═O)—, —S(═O)_(b)— or —NHS(═O)_(b)—, whereinb is 1 or 2;

V is —(CR^(2a)R^(2a))_(h)—, —O—(CR^(2a)R^(2a))_(h)—,—S—(CR^(2a)R^(2a))_(h)— or —NR^(2a)—(CR^(2a)R^(2a))_(h)—, wherein eachR^(2a), independently, is H, C₁₋₄alkyl or haloalkyl, and h is 1 or 2;

R² is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,indolinyl, indazolyl, indazolinyl, benzofuranyl, benzothiophenyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,benzoisothiazolyl, benzotriazolyl, tetrahydrofuranyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl,benzomorpholinyl, piperidinyl, piperazinyl, pyranyl, benzopyranyl,dioxozinyl and benzodioxolyl, said ring optionally substitutedindependently with 1-5 substituents of R⁷;

each R³, independently, is H, haloalkyl, CN or C₁₋₆-alkyl;

R⁴ is H, haloalkyl, CN or C₁₋₆-alkyl;

R⁵ is

wherein X¹ is CR⁸R⁸, C(═O), O, S, S(O)₂ or NR⁸;

each X², independently, is CR⁸R⁸;

-   -   each of Y¹ and Y², independently, is C₁₋₆-alkyl, —O—C₁₋₆-alkyl,        —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl or C₃₋₈-cycloalkyl;    -   alternatively Y¹ and Y² taken together with the carbon atom to        which they are attached form a partially or fully saturated 3,        4-, 5- or 6-membered spirocyclic ring, said ring formed of        carbon atoms optionally including 1-3 heteroatoms selected from        O, N and S and optionally substituted with 1-5 substituents of        R⁸, provided that said ring includes no more than two        heteroatoms selected from O, S and N;    -   Z² taken together with the carbon atoms to which it is attached        is a partially or fully unsaturated 5-6 membered monocyclic        ring, said ring formed of carbon atoms optionally including 1-3        heteroatoms selected from O, N and S;    -   m is 0, 1 or 2; and    -   p is 0, 1, 2, 3, 4 or 5

each R⁷, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, Cl₁—O— alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl;

each R⁸, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a saturated or partially or fullyunsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic, saidring system formed of carbon atoms optionally including 1-3 heteroatomsif monocyclic or 1-6 heteroatoms if bicyclic, said heteroatoms selectedfrom O, N, or S, wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of saidring system is optionally substituted independently with 1-5substituents of R⁹; and

R⁹ is halo, haloalkyl, CN, OH, NO₂, NH₂, oxo, acetyl, methyl, methoxyl,ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, benzyl, phenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl or a partially or fully saturated or unsaturated 3-6membered monocyclic formed of carbon atoms optionally including 1-3heteroatoms selected from O, N, or S, and optionally substitutedindependently with 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂,OH, oxo, acetyl, methyl, methoxyl, ethyl, ethoxyl, propyl, propoxyl,isopropyl, isopropoxyl, cyclopropyl, cyclopropylmethoxyl, butyl,butoxyl, isobutoxyl, tert-butoxyl, isobutyl, sec-butyl, tert-butyl,cyclobutyl, pentyl, cyclopentyl, hexyl, cyclohexyl, benzyl or phenyl.

In another embodiment, the compounds of Formula IV includes compoundswherein A is C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₁₋₆alkyl-O—C₁₋₃-alkyl-, C₁₋₆-alkyl-S—C₁₋₃-alkyl-,C₁₋₆-alkyl-S(O)₂—C₁₋₃-alkyl-, C₁₋₆-alkyl-NH—C₁₋₃-alkyl,di-(C₁₋₆-alkyl)-N—C₁₋₃-alkyl, C₂₋₆-alkenyl-O—C₁₋₃-alkyl-,C₂₋₆-alkenyl-S—C₁₋₃-alkyl-, C₂₋₆-alkenyl-S(O)₂—C₁₋₃-alkyl-,C₂₋₆-alkenyl-NH—C₁₋₃-alkyl- or C₂₋₆-alkynyl-NH—C₁₋₃-alkyl-, wherein thealkyl, alkenyl or alkynyl moiety of each is optionally substituted with1-3 substituents of R⁷;

W is —C(═O)—;

V is —(CR^(2a)R^(2a))_(h)— wherein each R², independently, is H, C₁-C₁₀alkyl or haloalkyl, and h is 1;

R² is ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl,thiadiazolyl, oxadiazolyl, indolyl, isoindolyl, benzofuranyl,benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzothiazolyl, benzoisothiazolyl, benzotriazolyl, pyrrolidinyl,oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl, benzomorpholinyl,benzopyranyl and benzodioxolyl, the ring optionally substituted with 1-3substituents of R⁷;

R³ is H, haloalkyl, CN, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl;

R⁴ is H, CN or C₁₋₁₀-alkyl;

R⁵ is

wherein each of A¹, A², A³ and A⁴, independently, is CR⁸ or N, providedthat no more than one of A¹, A², A³ and A⁴ is N;

-   -   m, X², Y¹ and Y² are as defined herein;    -   X¹ is CR⁸R⁸, O, S or S(O)₂; and    -   each Y³, independently, is CHR⁸, O, S or NR⁸;    -   o is 0, 1, 2 or 3; and    -   p is 0, 1, 2 or 3;

each R⁷, independently, is halo, haloalkyl, haloalkoxyl, CN, OH, NO₂,NH₂, acetyl, C₁₋₆-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₁₋₆-alkylamino-, C₁₋₆-dialkylamino-, C₁₋₆-alkoxyl or C₁₋₆-thioalkoxyl;and

each R⁸, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO₂,NH₂, acetyl, C₁₋₆-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₁₋₆-alkylamino-, C₁₋₆-dialkylamino-, C₁₋₆-alkoxyl or C₁₋₆-thioalkoxyl.

In yet another embodiment, the compounds of Formula IV includescompounds wherein R⁵ is

wherein each of A¹, A², A³ and A⁴, independently, is CR⁸ or N, providedthat no more than one of A¹, A², A³ and A⁴ is N;

X¹ is CR⁸R⁸, C(═O), O or NR⁸; and

each R⁸, independently, is H, halo, haloalkyl, haloalkoxyl, CN, OH, NO₂,NH₂, acetyl, C₁₋₆-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl,C₁₋₆-alkylamino-, C₁₋₆-dialkylamino-, C₁₋₆-alkoxyl or C₁₋₆-thioalkoxyl,in conjunction with any of the above or below embodiments.

In another embodiment, the compounds of Formula IV include compoundswherein X¹ is 0, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV includes compoundswherein X¹ is S, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV include compoundswherein X¹ is SO₂, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV includes compoundswherein X¹ is C(O), in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV include compoundswherein X¹ is CHR⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV includes compoundswherein X¹ is NR⁸, in conjunction with any of the above or belowembodiments.

In another embodiment, the compounds of Formula IV includes compoundswherein each R⁷, independently, is methyl, ethyl, propyl, isopropyl,butyl, isobutyl or sec-butyl as, in conjunction with any of the above orbelow embodiments.

In another embodiment, the compounds of Formula IV include eachindependent embodiment, as described herein for variables R^(1a),R^(1b), R^(1c), B, V, W, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, X¹, X², Y¹, Y², Y³and Z² for compounds of Formula I, independently, in conjunction withany of the above or below embodiments for compounds of Formula IV.

In another embodiment, the invention provides each of the Examplarycompounds, and stereoisomers, tautomers, solvates, pharmaceuticallyacceptable salts, derivatives or prodrugs thereof, and relatedintermediates, described herein.

In another embodiment, the invention provides the exemplified compoundsdescribed herein, and pharmaceutically acceptable salt forms of eachthereof.

Definitions

The following definitions should assist in understanding the inventiondescribed herein.

The term “comprising” is meant to be open ended, i.e., all encompassingand non-limiting. It may be used herein synonymously with “having.”Comprising is intended to include each and every indicated componentwhile not excluding any other components or elements.

The term “C_(α-β)alkyl”, when used either alone or within other termssuch as “haloalkyl” and “alkylamino”, embraces linear or branchedradicals having α to β number of carbon atoms (such as C₁-C₁₀; C₁-C₆; orC₁-C₄). Unless otherwise specified, one or more carbon atoms of the“alkyl” radical may be substituted, such as with a cycloalkyl moiety.Examples of “alkyl” radicals include methyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, ethyl, cyclopropylethyl,cyclobutylethyl, cyclopentylethyl, n-propyl, isopropyl, n-butyl,cyclopropylbutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,hexyl and the like.

The term “C_(α-β)alkenyl”, when used alone or in combination, embraceslinear or branched radicals having at least one carbon-carbon doublebond in a moiety having a number of carbon atoms in the range from α andβ. Included within alkenyl radicals are “lower alkenyl” radicals havingtwo to about six carbon atoms and, for example, those radicals havingtwo to about four carbon atoms. Examples of alkenyl radicals include,without limitation, ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations, as appreciated by those of ordinary skill in theart.

The term “C_(α-β)alkynyl”, when used alone or in combination, denoteslinear or branched radicals having at least one carbon-carbon triplebond in a moiety having a number of carbon atoms in the range from α andβ. Examples of alkynyl radicals include “lower alkynyl” radicals havingtwo to about six carbon atoms and, for example, lower alkynyl radicalshaving two to about four carbon atoms. Examples of such radicalsinclude, without limitation, ethynyl, propynyl (propargyl), butynyl, andthe like.

The term “C_(α-β)-alkyl”, “C_(α-β)-alkenyl” and “C_(α-β)-alkynyl”, whenused with other terms such as “wherein 1, 2 or 3 carbon atoms of saidC_(α-β)-alkyl, C_(α-β)-alkenyl or C_(α-β)-alkynyl is optionally replacedwith a heteroatom selected from O, S, S(O), S(O)₂ and N” embraces linearor branched radicals wherein one or more of the carbon atoms may bereplaced with a heteroatom. Examples of such “alkyl” radicals include—O-methyl, —O-ethyl, —CH₂—O—CH₃, —CH₂CH₂—O—CH₃, —NH—CH₂,—CH₂CH₂—N(CH₃)—CH₃, —S—(CH₂)₃CH₂, —CH₂CH₂—S—CH₃ and the like.Accordingly, such radicals also include radicals encompassed by —OR⁷where R⁷ may be defined as a C_(α-β)-alkyl. Examples of such “alkenyl”radicals include —NH—CH₂CH═CH₂, —S—CH₂CH₂CH═CHCH₃ and the like. Similarexamples exist for such “alkynyl” radicals, as appreciated by thoseskilled in the art.

The term “C_(α-β)alkoxyl” when used alone or in combination, embraceslinear or branched oxygen-containing alkyl radicals each having α to βnumber of carbon atoms (such as C₁-C₁₀). The terms “alkoxy” and“alkoxyl”, when used alone or in combination, embraces linear orbranched oxygen-containing radicals each having alkyl and substitutedalkyl portions of one or more carbon atoms. Examples of such radicalsinclude methoxy, ethoxy, propoxy, butoxy and tert-butoxy. Alkoxyradicals may be further substituted with one or more halo atoms, such asfluoro, chloro or bromo, to provide “haloalkoxy” radicals or with othersubstitution. Examples of such radicals include fluoromethoxy,chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy,fluoropropoxy and cyclopropylmethoxy.

The term “aryl”, when used alone or in combination, means a carbocyclicaromatic moiety containing one, two or even three rings wherein suchrings may be attached together in a fused manner. Every ring of an“aryl” multi-ring system need not be aromatic, and the ring(s) fused tothe aromatic ring may be partially or fully unsaturated and include oneor more heteroatoms selected from nitrogen, oxygen and sulfur. Thus, theterm “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, dihydrobenzafuranyl, anthracenyl, indanyl,benzodioxazinyl, and the like. The “aryl” group may be substituted, suchas with 1 to 5 substituents including lower alkyl, hydroxyl, halo,haloalkyl, nitro, cyano, alkoxy and lower alkylamino, and the like.Phenyl substituted with —O—CH₂—O— or —O—CH₂—CH₂—O— forms an arylbenzodioxolyl substituent.

The term “carbocyclic”, also referred to herein as “cycloalkyl”, whenused alone or in combination, means a partially or fully saturated ringmoiety containing one (“monocyclic”), two (“bicyclic”) or even three(“tricyclic”) rings wherein such rings may be attached together in afused manner and formed from carbon atoms. Examples of saturatedcarbocyclic radicals include saturated 3 to 6-membered monocyclic groupssuch as cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The terms “ring” and “ring system” refer to a ring comprising thedelineated number of atoms, the atoms being carbon or, where indicated,a heteroatom such as nitrogen, oxygen or sulfur. Where the number ofatoms is not delineated, such as a “monocyclic ring system” or a“bicyclic ring system”, the numbers of atoms are 3-8 for a monocyclicand 6-12 for a bicyclic ring. The ring itself, as well as anysubstitutents thereon, may be attached at any atom that allows a stablecompound to be formed. The term “nonaromatic” ring or ring system refersto the fact that at least one, but not necessarily all, rings in abicyclic or tricyclic ring system is nonaromatic.

The term “cycloalkenyl”, when used alone or in combination, means apartially or fully saturated cycloalkyl containing one, two or eventhree rings in a structure having at least one carbon-carbon double bondin the structure. Examples of cycloalkenyl groups include C₃-C₆ rings,such as compounds including, without limitation, cyclopropene,cyclobutene, cyclopentene and cyclohexene. The term also includescarbocyclic groups having two or more carbon-carbon double bonds such as“cycloalkyldienyl” compounds. Examples of cycloalkyldienyl groupsinclude, without limitation, cyclopentadiene and cycloheptadiene.

The term “halo”, when used alone or in combination, means halogens suchas fluorine, chlorine, bromine or iodine atoms.

The term “haloalkyl”, when used alone or in combination, embracesradicals wherein any one or more of the alkyl carbon atoms issubstituted with halo as defined above. For example, this term includesmonohaloalkyl, dihaloalkyl and polyhaloalkyl radicals such as aperhaloalkyl. A monohaloalkyl radical, for example, may have either aniodo, bromo, chloro or fluoro atom within the radical. Dihalo andpolyhaloalkyl radicals may have two or more of the same halo atoms or acombination of different halo radicals. Examples of haloalkyl radicalsinclude fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl,dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl, dichloroethyl and dichloropropyl. “Perfluoroalkyl”, asused herein, refers to alkyl radicals having all hydrogen atoms replacedwith fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “heteroaryl”, as used herein, either alone or in combination,means a fully unsaturated (aromatic) ring moiety formed from carbonatoms and having one or more heteroatoms selected from nitrogen, oxygenand sulfur. The ring moiety or ring system may contain one(“monocyclic”), two (“bicyclic”) or even three (“tricyclic”) ringswherein such rings are attached together in a fused manner. Every ringof a “heteroaryl” ring system need not be aromatic, and the ring(s)fused thereto (to the heteroaromatic ring) may be partially or fullysaturated and optionally include one or more heteroatoms selected fromnitrogen, oxygen and sulfur. The term “heteroaryl” does not includerings having ring members of —O—O—, —O—S— or —S—S—.

Examples of unsaturated heteroaryl radicals, include unsaturated 5- to6-membered heteromonocyclyl groups containing 1 to 4 nitrogen atoms,including for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl[e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl] andtetrazole; unsaturated 7- to 10-membered heterobicyclyl groupscontaining 1 to 4 nitrogen atoms, including for example, quinolinyl,isoquinolinyl, quinazolinyl, isoquinazolinyl, aza-quinazolinyl, and thelike; unsaturated 5- to 6-membered heteromonocyclic group containing anoxygen atom, for example, pyranyl, 2-furyl, 3-furyl, benzofuryl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, benzothienyl, etc.; unsaturated5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atomsand 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl,oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl,1,2,5-oxadiazolyl]; unsaturated 5 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example,thiazolyl, isothiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The term “heterocyclic”, when used alone or in combination, means apartially or fully saturated ring moiety containing one, two or eventhree rings wherein such rings may be attached together in a fusedmanner, formed from carbon atoms and including one or more heteroatomsselected from N, O or S. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered heteromonocyclic groups containing 1to 4 nitrogen atoms [e.g. pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, piperazinyl]; saturated 3 to 6-membered heteromonocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

The term “heterocycle” also embraces radicals where heterocyclicradicals are fused/condensed with aryl radicals: unsaturated condensedheterocyclic group containing 1 to 5 nitrogen atoms, for example,indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl,indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g.,tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Examples ofheterocyclic radicals include five to ten membered fused or unfusedradicals.

Examples of partially saturated and fully saturated heterocyclylsinclude, without limitation, pyrrolidinyl, imidazolidinyl, piperidinyl,pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The phrase “a saturated or partially or fully unsaturated 3-8 memberedmonocyclic or a 6-12 membered bicyclic, said ring system formed ofcarbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S” asused herein is intended to encompass all monocyclic and bicyclic ringsas small as three atoms to as large as 12 atoms in size, including bothcarbocyclic rings and heterocyclic, aromatic and non-aromatic rings. Thenon-aromatic rings may be partially or fully saturated in nature.

The term “alkylamino” includes “N-alkylamino” where amino radicals areindependently substituted with one alkyl radical. Preferred alkylaminoradicals are “lower alkylamino” radicals having one to six carbon atoms.Even more preferred are lower alkylamino radicals having one to threecarbon atoms. Examples of such lower alkylamino radicals includeN-methylamino, and N-ethylamino, N-propylamino, N-isopropylamino and thelike.

The term “dialkylamino” includes “N,N-dialkylamino” where amino radicalsare independently substituted with two alkyl radicals. Preferredalkylamino radicals are “lower alkylamino” radicals having one to sixcarbon atoms. Even more preferred are lower alkylamino radicals havingone to three carbon atoms. Examples of such lower alkylamino radicalsinclude N,N-dimethylamino, N,N-diethylamino, and the like.

The term “carbonyl”, whether used alone or with other terms, such as“aminocarbonyl”, denotes —(C═O)—. “Carbonyl” is also used hereinsynonymously with the term “oxo”.

The term “aminocarbonyl” denotes an amide group of the formula—C(═O)NH₂.

The term “alkylthio” or “thioalkoxy” embraces radicals containing alinear or branched alkyl radical, of one to ten carbon atoms, attachedto a divalent sulfur atom. An example of “alkylthio” or “thioalkoxy” ismethylthio, (CH₃S—).

The term “Formula I” includes any sub formulas, such as Formulas I-A,II, II-A, III-A, III-B or IV.

The term “pharmaceutically-acceptable” when used with reference to acompound of Formulas I-IV is intended to refer to a form of the compoundthat is safe for administration. For example, a salt form, a solvate, ahydrate, a prodrug or derivative form of a compound of Formulas I-IV,which has been approved for mammalian use, via oral ingestion or otherroutes of administration, by a governing body or regulatory agency, suchas the Food and Drug Administration (FDA) of the United States, ispharmaceutically acceptable.

Included in the compounds of Formulas I-IV are the pharmaceuticallyacceptable salt forms of the free-base compounds. The term“pharmaceutically-acceptable salts” embraces salts commonly used to formalkali metal salts and to form addition salts of free acids or freebases. As appreciated by those of ordinary skill in the art, salts maybe formed from ionic associations, charge-charge interactions, covalentbonding, complexation, coordination, etc. The nature of the salt is notcritical, provided that it is pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds ofFormulas I-IV may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, hydrofluoric, nitric, carbonic, sulfuric and phosphoricacid. Appropriate organic acids may be selected from aliphatic,cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic andsulfonic classes of organic acids, examples of which include, withoutlimitation, formic, acetic, adipic, butyric, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic,benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfonic,digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic,glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic,nicotinic, 2-naphthalenesulfonic, oxalic, palmoic, pectinic,persulfuric, 2-phenylpropionic, picric, pivalic propionic, succinic,thiocyanic, undecanoic, stearic, algenic, O-hydroxybutyric, salicylic,galactaric and galacturonic acid. Suitable pharmaceutically-acceptablebase addition salts of compounds of Formulas I-IV include metallicsalts, such as salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc, or salts made from organic bases including,without limitation, primary, secondary and tertiary amines, substitutedamines including cyclic amines, such as caffeine, arginine,diethylamine, N-ethyl piperidine, histidine, glucamine, isopropylamine,lysine, morpholine, N-ethyl morpholine, piperazine, piperidine,triethylamine, disopropylethylamine and trimethylamine. All of thesesalts may be prepared by conventional means from the correspondingcompound of the invention by reacting, for example, the appropriate acidor base with the compound of Formulas I-IV.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides, and others. Water or oil-soluble ordispersible products are thereby obtained.

Additional examples of such salts can be found in Berge et al., J.Pharm. Sci., 66:1 (1977). Conventional methods may be used to form thesalts. For example, a phosphate salt of a compound of the invention maybe made by combining the desired compound free base in a desiredsolvent, or combination of solvents, with phosphoric acid in a desiredstoichiometric amount, at a desired temperature, typically under heat(depending upon the boiling point of the solvent). The salt can beprecipitated upon cooling (slow or fast) and may crystallize (i.e., ifcrystalline in nature), as appreciated by those of ordinary skill in theart. Further, hemi-, mono-, di, tri- and poly-salt forms of thecompounds of the present invention are also contemplated herein.Similarly, hemi-, mono-, di, tri- and poly-hydrated forms of thecompounds, salts and derivatives thereof, are also contemplated herein.

The term “derivative” is intended to encompass any salt of a compound ofthis invention, any ester of a compound of this invention, or any othercompound, which upon administration to a patient is capable of providing(directly or indirectly) a compound of this invention, or a metaboliteor residue thereof, characterized by the ability to the ability tomodulate an enzyme.

The term “pharmaceutically-acceptable derivative” as used herein,denotes a derivative which is pharmaceutically acceptable.

The term “prodrug”, as used herein, denotes a compound which uponadministration to a subject or patient is capable of providing (directlyor indirectly) a compound of this invention. Examples of prodrugs wouldinclude esterified or hydroxylated compounds where the ester or hydroxylgroups would cleave in vivo, such as in the gut, to produce a compoundaccording to Formula I-IV. A “pharmaceutically-acceptable prodrug” asused herein, denotes a prodrug which is pharmaceutically acceptable.Pharmaceutically acceptable modifications to the compounds of FormulaI-IV are readily appreciated by those of ordinary skill in the art.

The compound(s) of Formulas I-IV may be used to treat a subject byadministering the compound(s) as a pharmaceutical composition. To thisend, the compound(s) can be combined with one or more excipients,including without limitation, carriers, diluents or adjuvants to form asuitable composition, which is described in more detail herein.

The term “excipient”, as used herein, denotes any pharmaceuticallyacceptable additive, carrier, adjuvant, or other suitable ingredient,other than the active pharmaceutical ingredient (API), which istypically included for formulation and/or administration purposes.“Diluent” and “adjuvant” are defined hereinafter.

The terms “treat”, “treating,” “treatment,” and “therapy” as used hereinrefer to therapy, including without limitation, curative therapy,prophylactic therapy, and preventative therapy. Prophylactic treatmentgenerally constitutes either preventing the onset of disordersaltogether or delaying the onset of a pre-clinically evident stage ofdisorders in individuals.

The phrase “effective dosage amount” is intended to quantify the amountof each agent, which will achieve the goal of improvement in disorderseverity and the frequency of incidence over treatment of each agent byitself, while avoiding adverse side effects typically associated withalternative therapies. Accordingly, this term is not limited to a singledose, but may comprise multiple dosages required to bring about atherapeutic or prophylactic response in the subject. For example,“effective dosage amount” is not limited to a single capsule or tablet,but may include more than one capsule or tablet, which is the doseprescribed by a qualified physician or medical care giver to thesubject.

The term “leaving group” (also denoted as “LG”) generally refers togroups that are displaceable by a nucleophile. Such leaving groups areknown in the art. Examples of leaving groups include, but are notlimited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g., mesylate,tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Nucleophiles are species that arecapable of attacking a molecule at the point of attachment of theleaving group causing displacement of the leaving group. Nucleophilesare known in the art. Examples of nucleophilic groups include, but arenot limited to, amines, thiols, alcohols, Grignard reagents, anionicspecies (e.g., alkoxides, amides, carbanions) and the like.

General Synthetic Procedures

The present invention further comprises procedures for the preparationof compounds of Formulas I-IV. The compounds of Formulas I-IV can besynthesized according to the procedures described in the followingSchemes 1, 2, 3a, 3b, 3c, 4, 5a, 5b and 5c, wherein the substituents areas defined for Formulas I-IV above, except where further noted. Thesynthetic methods described below are merely exemplary, and thecompounds of the invention may also be synthesized by alternate routesutilizing alternative synthetic strategies, as appreciated by persons ofordinary skill in the art. The following list of abbreviations usedthroughout the specification represent the following and should assistin understanding the invention:

-   ACN, MeCN—acetonitrile-   Aq., aq.—aqueous-   Ar—argon (gas)-   BOP—benzotriazol-1-yl-oxy Hexafluorophosphate-   BuLi—Butyllithium-   Cs₂CO₃—cesium carbonate-   CHCl₃—chloroform-   CH₂Cl₂, DCM—dichloromethane, methylene chloride-   Cu(1)I—copper(1) iodide-   DCC—dicyclohexylcarbodiimide-   DIC—1,3-diisopropylcarbodiimide-   DIEA, DIPEA—diisopropylethylamine-   DME—dimethoxyethane-   DMF—dimethylformamide-   DMAP—4-dimethylaminopyridine-   DMS—dimethylsulfide-   DMSO—dimethylsulfoxide-   EDC, EDCI—1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-   Et₂O—diethyl ether-   EtOAc—ethyl acetate-   FBS—fetal bovine serum-   G, gm—gram-   h, hr—hour-   H₂-hydrogen-   H₂O—water-   HATU—O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   HBr—hydrobromic acid-   HCl—hydrochloric acid-   HOBt—1-hydroxybenzotriazole hydrate-   HOAc—acetic acid-   HPLC—high pressure liquid chromatography-   IPA, IpOH—isopropyl alcohol-   K₂CO₃—potassium carbonate-   KI—potassium iodide-   LG—leaving group-   LDA—Lithium diisopropylamide-   LiOH—lithium hydroxide-   MgSO₄— magnesium sulfate-   MS—mass spectrum-   MeOH—methanol-   N₂— nitrogen-   NaCNBH₃-sodium cyanoborohydride-   Na₂CO₃— sodium carbonate-   NaHCO₃— sodium bicarbonate-   NaH—sodium hydride-   NaI—sodium iodide-   NaBH₄— sodium borohydride-   NaOH—sodium hydroxide-   Na₂SO₄—sodium sulfate-   NH₄Cl—ammonium chloride-   NH₄OH —ammonium hydroxide-   P(t-bu)₃—tri(tert-butyl)phosphine-   PBS—phospate buffered saline-   Pd/C—palladium on carbon-   Pd(PPh₃)₄—palladium(0)triphenylphosphine tetrakis-   Pd(dppf)Cl₂—palladium(1,1-bisdiphenylphosphinoferrocene) II chloride-   Pd(PhCN)₂Cl₂—palladium di-cyanophenyl dichloride-   Pd(OAc)₂— palladium acetate-   Pd₂(dba)₃—tris(dibenzylideneacetone) dipalladium-   PyBop—benzotriazol-1-yl-oxy-tripyrrolidino-phosphonium    hexafluorophosphate-   RT, rt—room temperature-   RBF, rbf—round bottom flask-   TLC, tic—thin layer chromatography-   TBAF—Tetrabutylammonium flouride-   TBTU—O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium    tetrafluoroborate-   TEA, Et₃N—triethylamine-   TFA—trifluoroacetic acid-   THF—tetrahydrofuran-   UW—ultraviolet light

While the synthetic strategy for preparing the compounds of FormulasI-IV may vary, as appreciated by persons skilled in the art, onestrategy for devising a method of making compounds of these formulas isby retro-synthetic disconnection. For example,

as shown in Formulas I-IV above, each squiggly line represents apossible point of bond-construction, whose order is generally dependentupon the particular compound being synthesized. Such bond constructionmethods are generally described in synthetic Schemes 1-5c below.

Scheme 1 describes a few methods for preparingC(R^(1a))(R^(1b))(R^(1c))—W acids, useful for preparing compounds ofFormulas I-IV (see scheme 2) wherein W is —C(O)— or —S(O)2- and each ofR^(1a), R^(1b) and R^(1c), independently, is C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, R1-C₁₋₁₀-alkyl-, R1-C₂₋₁₀-alkenyl- orR¹—C₂₋₁₀-alkynyl-(“L” in scheme 1 corresponds to the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl or C₂₋₁₀-alkynyl of A defined in A-W above or ofC(R^(1a))(R^(1 b))(R^(1c)) defined herein). DesiredC(R^(1a))(R^(1b))(R^(1c))—W groups and A-W groups may be commerciallyavailable and purchased, or may be made by known, conventional methods.As shown, esters 1 can be hydrolyzed to their corresponding acids 2using known bases, such as NaOH or LiOH. Acids 2 can then be coupled toan amine (not shown) to prepare compounds of Formula I-IV. Similarly,sulfonic acids 1′ can be converted to an activated sulfonate 2′ byreaction with oxalyl chloride, for example, to prepare the correspondingsulfonyl chloride 2′. The sulfonyl chloride 2′ can be reacted with anamine to prepare compounds of Formula I-IV.

Desired C(R^(1a))(R^(1b))(R^(1c))—W groups of Formulas I, II, II-A,III-A and III-B and A-W groups of Formula IV, which may be substitutedwith various substitutions including one or more R⁷ groups, can becoupled to the core hydroxyl-propyl backbone structure, generallydesignated in Scheme 2 as “Pr” group, by various coupling methods asdescribed in Scheme 2. In each of the 4 sub-schemes, X refers generallyto a “LG” or a “leaving group” such as a halide (bromine, chlorine,iodine or fluorine), alkylsulfonate and other known groups (also seedefinitions herein) which generally forms an electrophilic species (E⁺)and m is an integer from 0-1. The NH₂ group (primary amine) is anucleophilic species (Nu⁻), as is secondary amines, hydroxides,alkoxides, an anionic carbon species and the like, which should besufficiently strong to the attack the E⁺ species and displace theleaving group X thereby effecting a coupling of A-W to the Pr backbone.Examples of suitable electrophilic carbonyl species include, withoutlimitation, acid halides, mixed anhydrides, aldehydes,carbamoyl-chlorides, sulfonyl chlorides, acids activated by couplingwith activating reagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP andcarbodiimides (DCC, EDC and the like), and other electrophilic speciesincluding halides, isocyanates, daizonium ions and the like.

The coupled adduct of C(R^(1a))(R^(1b))(R^(1c))—W and Pr or A-W and Pr,shown as products in sub-schemes 1-4, can be brought about using variousconventional methods. For example, an amide or a sulfonamide linkage, asshown in sub-schemes 2 and 4, can be made utilizing an amine on the Printermediate and an activated electrophilic species, on the A-W groupsuch as the acid chloride or sulfonyl chloride as shown. The reactionproceeds generally in the presence of a suitable solvent and/or base.Suitable solvents include, without limitation, generallynon-nucleophilic, anhydrous solvents such as toluene, CH₂Cl₂, THF, DMF,N,N-dimethylacetamide and the like, including solvent combinationsthereof. The solvent may range in polarity, as appreciated by thoseskilled in the art. Suitable bases include, for example, tertiary aminebases such as DIEA, TEA, carbonate bases such as Na₂CO₃, K₂CO₃, Cs₂CO₃,hydrides such as NaH, KH, borohydrides, cyanoborohydrides and the like,alkoxides such as NaOCH₃, and the like. The base itself may also serveas a solvent. The reaction may optionally be run neat, i.e., without anybase and/or solvent. These coupling reactions are generally fast andconversion occurs typically in ambient conditions. However, dependingupon the particular substrate, such reactions may require heat, asappreciated by those skilled in the art.

Similarly, carbamates as illustrated in sub-scheme 1 and ureas asillustrated in sub-scheme 3 may be made as shown, wherein X has the samedefinition as above, using the same coupling methods described above forsub-schemes 2 and 4. While the above methods are so described, they arenot exhaustive, and other methods for linkingC(R^(1a))(R^(1b))(R^(1c))—W groups and A-W groups and desired Pr groupstogether may be utilized as appreciated by those skilled in the art.

The coupling methods described in sub-schemes 1-4 of scheme 2 are alsoapplicable for coupling desired C(R^(1a))(R^(1b))(R^(1c))—W and A-Wintermediates to desired Pr intermediates not containing desired R⁵groups, although sub-schemes 1-4 as illustrated do contain R⁵ groups.

Amine intermediate 9 (one embodiment of an R⁵ ring of the compounds ofFormula I) can be prepared according to the method generally describedin Scheme 3a. As shown, spiro-substituted-(ring Z) orgem-dialky-substituted (not shown) oxo-R⁵ ring intermediates 6 (shownwhere R⁵ of Formula I is a spiro fused chroman or aza-chroman ring, asin Formulas II, II-A, III-A and III-B) can be converted directly to theamino-intermediate 9 using known reductive amination methods, such as inthe presence of sodium cyanoborohydride and ammonium acetate.Alternatively, the carbonyl may be reduced to the corresponding alcoholusing conventional reducing reagents or catalytic hydrogenationconditions, and then converted to form the correspondingazido-intermediate 8 using known reagents, such as DPPA, in the presenceof a suitable base as shown. Intermediate 8 may be reduced with asuitable reducing agent or by known methods, includingtriphenylphosphine, trimethylphosphine or lithium aluminum hydride(LAH), to produce the desired amino adduct 9.

Yet another method of forming the amine adduct 9, can be via an imineformation to form compound 10. The imine double bond of compound 10 maythen be successively reduced and deprotected to yield the primary amineproduct 9. Such steps may be conducted using known, conventionalmethods, as appreciated by those skilled in the art.

Alternatively, amine intermediates 9 may be prepared by the method shownin scheme 3b above. Desirably substituted compounds 9a may first betreated with a strong base, such as LDA or n-butyl lithium, to form ananion that may then be added to a sufinylimine intermediate 9b(nucleophilic group X may be protected or unprotected as appreciated byone of ordinary skill in the art) to form the corresponding coupledadduct 9c. Open intermediate 9c (X may first be deprotected asnecessary) may subsequently be treated with a strong base, such as NaH(wherein, e.g., X is a nucleophile such as OH or NHR⁶) or TBAF (wherein,e.g., X is OSiR₃) to form intermediate 11. Intermediate 11 may then bedeprotected to provide spiro amine compound 9.

Amine intermediate 9 can also be prepared from other amine 9 precursorssuch as 9d containing an appropriate leaving group (LG, e.g., Cl, Br, I,OTf, etc) as shown in scheme 3c above. Using this method, compound 9d,with the amino group used as is, mono-protected (compound 9e), or doublyprotected (compound 9f having PG1 and PG2 protecting groups as shown),can be coupled with the requisite neucleophilic reagents with a catalystsuch as a Pd-catalyst selected from appropriate sources. The saidneucleophilic reagents can be selected from, but not limited to,commercial or pre-formed boronic reagents, stannane reagents, Zinc- orMagnesium-derived metallic reagents. After deprotection if necessary,amine intermediate 9 can be obtained.

Scheme 4a describes, generally, multiple different methods forconstructing the bond between the amino-propyl backbone startingmaterial (also referred to herein as “Pr”) or intermediate 12′(sub-scheme 1) or 12 (sub-scheme 2) and an R⁵ ring intermediate 9,thereby synthesizing a desired intermediate 14′ or a final compound 14of Formulas I-IV (as shown, R² of Formula I is a substituted phenylring. As appreciated, the scope of the invention is not so limited, andR² can also be other rings, such as pyridine, as defined and/orexemplified herein). One method to make this bond is to react an epoxideintermediate 12 or 12′ (Note: the epoxide 12 or 12′ may be purchasedcommercially or made via known, published methods such as from theolefin precursor), with an amino-R⁵ intermediate 9, as shown. Thereaction may proceed in the presence of a polar solvent, such as analcohol or dioxanes, and may require additional reagents, as appreciatedby those skilled in the art. Additionally, the reaction may require heatfor a period of time. Note that while the scheme described the additionof heat, this is by way of example only, and not every reaction wouldnecessarily require heat, as appreciated by those of ordinary skill inthe art. The protecting group may be removed using an acid, such as HCR,such that the bonded adduct 14′ is recovered as an HCl salt.

Alternatively, desired intermediates 14′ may be synthesized startingwith an amine-protected aldehyde intermediate 13′ (sub-scheme 3) or 13(sub-scheme 4) and condensing the aldehyde with a primary or secondaryamine 9 to form an imine (not shown, generally formed in-situ and notisolated). The imine can then be reduced using a known reducing agent,such as a hydride or borohydride, the reduced intermediate may bedeprotected to provide an intermediate 14′ having an amine useful toprepare compounds 14 of Formulas I-IV.

Scheme 4b describes, generally, a method for preparing analogs ofintermediate 20, which locks in a desired benzodioxoyl R² group with adesired R⁵ group, as defined in Formulas I-IV. The strategy, as shown,generally involves use of an internal tether to provide the desiredintermediate 20. Intermediate 15, where X is a leaving group such as ahalogen (chloride for example) and P is a protecting group, can bereacted with the isocyanate of a desired R⁵-amine 16, such as chromans,aza-chromans, and the like described in the definitions of R⁵ herein, toafford the halo-carbamate 17. The amine of carbamate 17 can be used tointernally displace leaving group X to form a tethered cyclicintermediate 18. The tethered ring of 18 can be opened to afford desiredamine protected intermediate 19. The protecting group may be removedusing an acid such as HCl (or base or other suitable conditionsdepending upon the protecting group used) such that the amine adduct 20is recovered as an HCl salt.

Scheme 4c describes, generally, another method for preparing analogs ofintermediate 20, which locks in a desired benzodioxyl R² group with adesired R⁵ group, as defined in Formulas I-IV. As shown, the desiredtethered intermediate 18b may be formed in another way. For example, andas shown in scheme 4c, an activated carbonated form of intermediate 16b(without the NH—R⁵) could react with the desired amine to form the open,untethered intermediate 17b. For instance, a desired chlorohydrin 15(scheme 4b) can be acylated with 4-nitrophenylchloroformate to generatean active carbonate (not shown). This active carbonate should readilyreact with a desired chromyl amine or azachromyl amine fragment (NH₂—R⁵)to form the chlorourethane 17b (where X is Cl and Y is C(O)).Cyclization of this intermediate without isolation affords theoxazolidinone 18b which then can be deprotected to form the intermediateoxazolidinone bis hydrochloride salt 19. The amine of salt 19 can befurther deprotected and isolated as the tris-HCl salt useful forpreparing compounds of Formulas I-IV.

Another example may utilize a different activating agent, such as1,1′-carbonyldiimidazole, in place of 4-nitrophenylchloroformate to forman activated chlorohydrin or halohydrin type intermediate, whichfunctions similar to intermediate 17.

Scheme 5a describes, generally, one method for constructing gem-dialkylor spiro Z ring compounds (not shown) 9 in schemes 3a and 3b above, byfirst preparing the corresponding bromo-intermediate 25 as schematicallyillustrated above. As shown, a methoxy pyridine compound 21 can bereacted with a bromine source, such bromine in HOAc, in the presence ofan acid to form the corresponding dibrominated intermediate 22. Compound22 can be treated with a suitably strong base, such as a lithium base(e.g. BuLi) in the presence of a suitable non-protic, anhydrous colvent,such as ether, to form the lithiated species, which may then be treatedwith a suitable aldehyde, such as the allylic aldehyde shown above, toafford the corresponding alcohol adduct 24. Intermediate 24 may then betreated with a suitable acid, such as HBr, to protonate and condense thecompound effecting ring closure to afford the cyclized adduct 25.

Scheme 5b describes, generally, another method for constructinggem-dialkyl (not shown) or spirocyclobutane Z ring compounds (shown) 9in schemes 3a and 3b above, by first preparing the correspondingbromo-keto-intermediate 31 as schematically illustrated above. As shown,a methoxy picolinic acid 26 can be reacted with an aqueous brominesource, such bromine, in the presence of a suitable solvent, such asDCM/water, to form the corresponding brominated intermediate 27. Theacid group of compound 27 can be converted to the corresponding Weinrebamide under known conditions, such as using EDC-HCl in the presence ofHOBt, a base such as TEA, and a suitable solvent such as DCM. Weinreb 28may be treated with a desired Grignard reagent, such as vinylmagnesiumbromide as shown above, in the presence of a suitable solvent, such asTHF, to form the allylic ketone species 29. Alternatively, the Weinrebamide species may be bypassed by treating compounds 28 directly with theGrignard reagents, such the one shown above, to afford compounds 29.Compound 29 can undergo a Grubb's metathesis, such as by utilizingexo-methylene cyclobutane as shown above, to form intermediate 30, whichmay then be cyclized to ring closure using a suitable acidicenvironment, such as in EtOH/HCl, to provide the desired compounds 31.An additional method to prepare mono-substituted aza-chroman compounds,but not gem-dialkyl or spiro aza-chroman compounds 31 is described inSarges et at, J. Med. Chem., 1990, 33, 1859-1865, which disclosure ishereby incorporated herein by reference in its entirety. Theketo-intermediate 31 can then be converted to the corresponding primaryamino species using the chemistry taught herein.

Scheme 5c describes, generally, yet another method for constructinggem-dialkyl (not shown) or spirocyclobutane Z ring intermediates (shown)30 in scheme 5b above. Compound 30 in turn may be converted to thedesired bromo-keto-intermediate 31 as schematically illustrated above.As shown, brominated intermediate 27 from scheme 5b can be treated withan acid, such as sulfuric acid as shown, in a protic solvent, such asMeOH, to form the corresponding methyl ester intermediate 32. The estergroup of compound 32 can be converted to the corresponding phosphonateester under Horner-Emmons type conditions, which are known in the art,such as using a phosphonate species in the presence of a strong base,such as LiHMDS as shown, and a suitable solvent such as THF and toluene.The resulting phosphonate adduct 33 may be deprotonated with a strongbase, such as with liOMe in the presence of an alcoholic solvent such asMeOH and/or i-PrOH, and the lithium enolate can then be reacted withcyclobutanone to afford the adduct compound 30 in high yield.Intermediate 30 may then be cyclized to ring closure using suitableconditions, such as those shown above in scheme 5c, to provide thedesired compounds 31. Additional description of useful methods which maybe used to prepare compounds similar to compound 31 are described ingeneral in Harada et at, JP patent application no. JP08099982A, Yasudaet al, J. Org. Chem. 2004, 69, pg 1958, Yazbeck et al, Org. Process Res.Dev. 2006, 10, pg 655, and in Keneko et al, Chem. Pharm. Bull., 2004,52, pg 675, which disclosures are hereby incorporated herein byreference in its entirety. The keto-intermediate 31 can then beconverted to the corresponding primary amino species using the chemistrytaught herein.

It should be appreciated that schemes 5a, 5b and 5c illustrate exemplarymethods for preparing the right-side spiro or gem-dialkyl pieces ofcompounds of Formulas I-IV. Reaction yields for each step in schemes 5aand 5b range from about 50% to 90+%. Accordingly, these methods mayprovide a more efficient process for preparing desired intermediates 31.Further, utilizing these methods may afford other spirocyclic rings ofdiffering sizes and heteroatoms, encompassed in the compounds of thepresent invention.

To enhance the understanding and appreciation of the present invention,the following specific examples (starting reagents, intermediates andcompounds of Formulas I-IV) are set forth. The following analyticalmethods were used to purify and/or characterize the compounds, andintermediates, described in the examples below.

Chromatography: Unless otherwise indicated, crude product-containingresidues were purified by passing the crude material or concentratethrough an ISCO brand silica gel column (pre-packed or individuallypacked with SiO₂) and eluting the product off the column with a solventgradient as indicated. For example a description of (330 g SiO₂, 0-40%EtOAc/Hexane) means the product was obtained by elution from the columnpacked with 330 gms of silica, with a solvent gradient of 0% to 40%EtOAc in Hexanes.Preparative HPLC Method:

Unless otherwise indicated, the compounds described herein were purifiedvia reverse phase HPLC using one of the following instruments: Shimadzu,varian, Gilson; utilizing one of the following two HPLC columns: (a) aPhenomenex Luna or (b) a Gemini column (5 micron or 10 micron, C18,150×50 mm)

A typical run through the instrument included: eluting at 45 ml/min witha linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water(0.1% TFA) over 10 minutes; conditions can be varied to achieve optimalseparations.

Proton NMR Spectra:

Unless otherwise indicated, all ¹H NMR spectra were run on a Brukerseries 300 MHz instrument or a Bruker series 400 MHz instrument. Whereso characterized, all observed protons are reported as parts-per-million(ppm) downfield from tetramethylsilane (TMS) or other internal referencein the appropriate solvent indicated.

Mass Spectra (MS)

Unless otherwise indicated, all mass spectral data for startingmaterials, intermediates and/or exemplary compounds are reported asmass/charge (m/z), having an (M+H⁺) molecular ion. The molecular ionreported was obtained by electrospray detection method (commonlyreferred to as an ESI MS) utilizing a PE SCIEX API 150EX MS instrumentor an Agilent 1100 series LC/MSD system. Compounds having an isotopicatom, such as bromine and the like, are generally reported according tothe detected isotopic pattern, as appreciated by those skilled in theart.

The compounds disclosed and described herein have been named usingeither (1) the naming convention provided with Chem-Draw Ultra 8.0software, available in Chem Office, or (2) by the ISIS database software(Advanced Chemistry Design Labs or ACD software). In some instances,compounds were named with the term “spirocarbocycle” inserted whereappropriate. For example, where the chroman is substituted with2,2-spirocyclobutyl, “2,2-spirocyclobutyl” have been added to theChem-Draw nomenclature in the appropriate place.

EXAMPLES

The Examples, described herein below, represent various exemplarystarting materials, intermediates and compounds of Formulas I-IV, whichshould assist in a better understanding and appreciation of the scope ofthe present invention and of the various methods which may be used tosynthesize compounds of Formulas I-IV. It should be appreciated that thegeneral methods above and specific examples below are illustrative only,for the purpose of assistance and of understanding the presentinvention, and should not be construed as limiting the scope of thepresent invention in any manner.

Example 1

(4S,5S)-tert-Butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)oxazolidine-3-carboxylateStep 1: (S)-Methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyridin-4-yl)propanoate

The title compound was prepared according to previously reportedprocedure (see pending U.S. patent application Ser. No. 11/575,187) from(R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate and4-iodo-2-(trifluoromethyl)pyridine (this starting material was preparedaccording to a procedure described in Eur. J. Org. Chem. 2003,1559-1568).

Step 2: (4S,5S)-tert-Butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)oxazolidine-3-carboxylate

The title compound was prepared according to procedure described in U.S.patent application Ser. No. 11/575,187, from (S)-methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyridin-4-yl)propanoate.

Example 2

tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[d][1,3]dioxol-5-yl)-4-oxobutan-2-ylcarbamateStep 1: (S)-tert-Butyl3-(7-chlorobenzo[d][1,3]-dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)propan-2-ylcarbamate

A solution of 2-bromothiazole (3 ml, 37 mmol) in ether (75 mL) wascooled to −78° C. and treated with n-butyllithium 2M in hexanes (18 ml,37 mmol). After stirring the reaction for 30 minutes, a solution of(S)-methyl2-(tert-butoxycarbonyl)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)propanoate(6.610 g, 18 mmol) in ether (75 mL) was added, and the reaction mixturewas allowed to stir at −78° C. for 1 hour. The reaction mixture wasquenched with saturated NH₄Cl solution, washed with water and brine. Theorganic layers were dried over MgSO₄ and concentrated under reducedpressure. Purification of the crude residue by column chromatographygave (S)-tert-butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)propan-2-ylcarbamate(4.22 g, 56% yield) as a yellow oil.

Step 2: tert-Butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate

A cooled solution (0° C.) of (S)-tert-butyl3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-oxo-1-(thiazol-2-yl)propan-2-ylcarbamate(4.220 g, 10 mmol) in EtOH (60 mL) was added dropwise via cannula to acooled solution (−78° C.) of lithium tri-tert-butoxyaluminum hydride 1Min THF (21 ml, 21 mmol) in EtOH (40 mL). After stirring for 2 hours, thereaction mixture was quenched with 1N HCl and diluted with EtOAc. Theorganic layer was washed with water, saturated NaHCO₃ solution, andbrine. The organic layer was dried over MgSO4 and concentrated underreduced pressure. The crude residue was crystallized from hot EtOH/waterand the solid was collected yielding tert-butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate(3.250 g, 77% yield) as a white solid.

Step 3: tert-Butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate

A suspension of tert-butyl(1S,2S)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-hydroxy-1-(thiazol-2-yl)propan-2-ylcarbamate(3.250 g, 8 mmol) in DCM (24 mL) was treated with 2,6-lutidine (1 ml, 12mmol) followed by tert-butyldimethylsilyl triflate (2 ml, 9 mmol) andwas allowed to stir at RT for 2 hours. An additional equivalent of TBStriflate was added followed by an additional equivalent of base. After 1hour, DIEA (2 ml, 12 mmol) was added, followed bydi-tert-butyldicarbonate 1M in THF (8 ml, 8 mmol), and the reactionmixture was allowed to stir at RT overnight. The reaction mixture wasquenched with 2N HCl solution, diluted with DCM, and washed withsaturated NaHCO₃ solution and brine. The organics were dried over MgSO₄and concentrated under reduced pressure. Purification of the cruderesidue by column chromatography gave tert-butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate(1.850 g, 45% yield).

Step 4: tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[d][1,3]dioxol-5-yl)-4-oxobutan-2-ylcarbamate

A solution tert-butyl(1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(7-chlorobenzo[d][1,3]dioxol-5-yl)-1-(thiazol-2-yl)propan-2-ylcarbamate(1.85 g, 3.51 mmol) in MeCN(14 mL) was treated with 4 A mol. seives andwas allowed to stir at RT for 10 minutes. Methyltrifluoromethanesulfonate (0.464 ml, 4.21 mmol) was added, and thereaction mixture was allowed to stir for 30 minutes. The reactionmixture was then concentrated under reduced pressure, and the cruderesidual material was dissolved in MeOH(14 mL), and cooled to 0° C. Themixture was then treated with sodium borohydride (0.398 g, 10.5 mmol)and allowed to warm to RT and stir for an additional 20 minutes. Thereaction mixture was diluted with EtOAc, filtered through celite andconcentrated under reduced pressure. The residue was dissolved in ACN(10mL) and water (4 mL) and was treated with mercury(II) chloride (0.953 g,3.51 mmol). After stirring for 30 minutes the reaction mixture wasdiluted with ether and filtered through a short plug of silica. Thefiltrate was then concentrated under reduced pressure and the cruderesidue was purified by column chromatography yielding tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(7-chlorobenzo[d][1,3]dioxol-5-yl)-4-oxobutan-2-ylcarbamate.

Example 3

tert-Butyl(2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2-ylcarbamateStep 1:N-((2S,3S)-1-(benzo[d][1,3]dioxol-4-yl)-3,4-bis(tert-butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide

To a slurry of magnesium turnings (1.09 g, 44.8 mmol) in 5 mL of THF wasadded iodine (0.0650 g, 0.256 mmol), followed by a solution of5-(chloromethyl)benzo[d][1,3]dioxole (6.55 g, 38.4 mmol) in 30 mL ofTHF. After 1 minute, the exothermic reaction mixture was placed in anice bath for 1 minute and then stirred at ambient temperature for 1hour. TMEDA (7.68 ml, 51.2 mmol) was added to the reaction and themixture was cooled to −78° C. for 5 minutes at which point a solution of(E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide(5400 mg, 12.8 mmol) in 25 mL THF was added via a syring pump over 15minutes. The reaction was allowed to warm to RT over the course of 2hours then stirred at RT for an additional hour. The mixture was dilutedwith ethyl acetate (100 mL) and poured in saturated ammonium chloride(250 mL). The aqueous layer was extracted with ethyl acetate (2×250 mL)and the combined organic layers were washed with water and then brineand dried over Na₂SO₄. The organic convents were filtered, concentratedunder reduced pressure and the crude material was purified by silica gelto provideN-((2R,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3,4-bis(tert-butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide(4.51 g, 63.1% yield) as a colorless oil.

Step 2: tert-Butyl(2S,3S)-1-(benzo[d][1,3]dioxol-4-yl)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2-ylcarbamate

To a solution ofN-((2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3,4-bis(tert-butyldimethylsilyloxy)butan-2-yl)-2-methylpropane-2-sulfinamide(2300 mg, 4 mmol) in 25 mL of ethanol at 0° C. was added 4M HCl indioxane (6 ml, 25 mmol). After stirring at 0° C. for a total of 7 hours,TEA (4 ml, 29 mmol) was added dropwise followed by addition of 25 mL ofDCM and di-tert-butyl dicarbonate (2 g, 9 mmol). The mixture was stirredat rt for 48 hours, then diluted with DCM (50 mL) and poured insaturated ammonium chloride (250 mL). The aqueous layer was extractedwith DCM (4×100 mL). The combined organic layers were washed with waterand brine and dried over Na₂SO₄, filtered and concentrated under reducedpressure, to provide an oil that was flashed through a plug of silicagel to provide tert-butyl(2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2-ylcarbamateas a colorless oil.

Example 4

(4S,5S)-tert-Butyl4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateStep 1: (S)-Methyl2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate

To a 25 mL RBF was added zinc powder (1.03 g, 15.8 mmol) and iodine(0.0161 g, 0.0633 mmol). The mixture was heated with a heat gun for 5minutes and the resulting mixture was then flushed with nitrogen 3 timesand allowed to cool to rt. A solution of (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate (3.47 g, 10.5 mmol) in 5 mL ofDMF was added dropwise to the mixture over 3 minutes and the resultinggrey slurry was stirred at 0° C. for 20 minutes before being warmed tort. After stirring at rt for 30 minutes,5-bromo-2,2-difluorobenzo[d][1,3]dioxole (2.50 g, 10.5 mmol), Pd₂(dba)₃(0.193 g, 0.211 mmol) and S(Phos) (0.346 g, 0.844 mmol) were added andthe reaction mixture was heated to 40° C. for 2 hours. The resultingmixture was cooled to rt and partitioned between ethyl acetate (50 mL)and a solution of ˜9:1 saturated ammonium chloride/ammonium hydroxidepH=9 (250 mL). The aqueous layer was extracted with ethyl acetate (3×100mL) and the combined organic layers were washed with water, brine, anddried over sodium sulfate. Concentration of the filtered solvents andpurification of resulting crude material by silica gel chromatographyprovided (S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate(1.89 g, 49.9% yield) as a slightly brown oil.

Step 2:(S)-2-(tert-Butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoicacid

To a solution of (S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoate(1850 mg, 5 mmol) in 50 mL of THF at 0° C. was added LiOH (0.2 M, 26 ml,5 mmol) over 10 minutes. The reaction was stirred for 2 hours and wasthen washed with ether (200 mL), acidified to pH 4 with 2 N HCl andextracted with ethyl acetate (4×100 mL). The organics were washed withwater and brine and dried over sodium sulfate. Concentration provided(S)-2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoicacid (1.75 g, 98% yield) as a colorless oil.

Step 3:(S)-3-(tert-Butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate

To a solution of(S)-2-(tert-butoxycarbonyl)-3-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)propanoicacid (1650 mg, 5 mmol) in 50 mL of THF at 0° C. was added TEA (0.7 ml, 5mmol) and isobutyl chloroformate (0.6 ml, 5 mmol). The reaction mixturewas stirred at 0° C. for 1.5 hours then filtered through a fritcontaining celite. The solution was cooled to 0° C. and treated withfreshly prepared diazomethane (0.5 M in ether, 14 ml, 7 mmol). Afterstirring for 1 hour at 0° C. the reaction was poured into saturatedsodium bicarbonate 250 mL and the aqueous layer was extracted with ethylacetate (3×100 mL). The combined organic layers were washed with waterand then brine and dried over Na₂SO₄. Concentration of solvents underreduced pressure provided the diazo ketone as a yellow solid that wascarried on without further purification. The derived diazo ketone wastaken up in 50 mL of THF and cooled to 0° C. at which point hydrobromicacid, 33 wt. % in acetic acid (0.7 ml, 12 mmol) was added dropwise over1 minute. After stirring at 0° C. for 1 hour potassium carbonate (1.0 g,7 mmol) and sodium acetate (4 g, 48 mmol) were added to the mixture. TheTHF was removed in vacuo and 15 mL of DMF was added to the reaction. Theresulting slurry was stirred for 10 minutes at which point the reactionmixture was diluted with ethyl acetate (50 mL) and poured in water 100mL. The aqueous layer was extracted with ethyl acetate (2×100 mL). Thecombined organic layers were washed with water and then brine and driedover Na₂SO₄. Concentration of the solvents under reduced provided(S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (1.10 g, 57% yield) as a white solid.

Step 4:(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate

A solution of(S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (1100 mg, 2741 μmol) in 45 mL of ethanol cooled to 0° C. wasadded to lithium aluminumtri-tert-butoxyhydride (1 M in THF, 5481 μl,5481 μmol) in 15 mL of ethanol at −78° C. dropwise via cannula over 5minutes. After stirring at −78° C. for 2 hours the reaction was quenchedwith 10 mL of 1 N HCl and the mixture was diluted with ethyl acetate(500 mL). The reaction was poured into 200 mL of water, the layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×100mL). The combined organics were washed with water, brine, and dried oversodium sulfate, filtered and concentrated to provide(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (1060 mg, 96% yield) as a white solid.

Step 5: (4S,5S)-tert-butyl4-((2,2-difluorobenzo[d][1,3]-dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate

To a solution of(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (1050 mg, 2603 μmol) in 5 mL of DMF was added 2-methoxypropene(872 μl, 9111 μmol) and CSA (181 mg, 781 μmol). The mixture was stirredat rt overnight, and 91 mg of CSA and 0.872 mL of 2-methoxypropene wereadded. The reaction was stirred for 2 hours, then poured into ice-coldaqueous saturated sodium bicarbonate (150 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were washed with water,brine, and dried over sodium sulfate. The derived yellow oil was takenup in 10 mL of methanol cooled to 0° C. and treated with potassiumcarbonate (1079 mg, 7809 μmol). After warming to rt over the course of 1hour the reaction was diluted with ethyl acetate (25 mL) and poured insaturated ammonium chloride (50 mL). The aqueous layer was extractedwith ethyl acetate (3×50 mL) and the combined organic layers were washedwith water and then brine and dried over Na₂SO₄. Concentration of thesolvents under reduced pressure and purification by silica gel provided(4S,5S)-tert-butyl4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateas a colorless oil.

Example 5

(4S,5S)-tert-Butyl4-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateStep 1: (Z)-Methyl2-(tert-butoxycarbonyl)-3-(2-methylbenzo[d][1,3]dioxol-5-yl)acrylate

To a solution of methyl2-(tert-butoxycarbonyl)-2-(dimethoxyphosphoryl)acetate (5255 mg, 17678μmol) in 25 mL of DCM at 0° C. was added DBU (2665 μl, 17678 μmol)dropwise. To the mixture was then added a solution of2,2-dimethylbenzo[d][1,3]dioxole-5-carbaldehyde (3000 mg, 16836 μmol) in10 mL of DCM over 5 minutes so as to maintain internal temperature below10° C. The reaction was warmed to rt and stirred overnight before beingdiluted with DCM (25 mL) and poured in saturated ammonium chloride (100mL). The aqueous layer was extracted with DCM (1×50 mL). The combinedorganic layers were washed with 10% aqueous sodium bicarbonate thenwater then brine and dried over Na₂SO₄. Concentration under reducedpressure and purification by silica gel provided (Z)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate(5005 mg, 85.1% yield) as a white solid.

Step 2: (S)-Methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate

To a slurry of (Z)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)acrylate(5000 mg, 14311 μmol) in 30 mL of MeOH was added [(1S,1S,2R,2R′)Rh(duanphos)cod]BF₄ (101.1 mg, 143.1 μmol) followed by an additional 15mL of methanol. The mixture was purged with hydrogen 3 times and thensealed at 50 psi of H₂After 3 hours reaction the reaction wasconcentrated and purified by silica gel chromatography to provide(S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate(5000 mg, 99.43% yield) as a colorless oil.

Step 3:(S)-2-(tert-Butoxycarbonyl)-3-(2,2-dimethylbenzo[d][113]dioxol-5-yl)propanoicacid

To a solution of (S)-methyl2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoate(5000 mg, 14229 μmol) in 100 mL of THF at 0° C. was added lithiumhydroxide (0.2 M, 28458 μl, 14229 μmol) over 10 minutes. After stirringat 0° C. for 1 hour the reaction was poured into a separatory funnel and100 mL of water was added. The mixture was washed with 150 mL of ether,then acidified to pH 2-3- with 1 N HCl. Ethyl acetate was added, thelayers were separated and the aqueous layer was extracted with ethylacetate (3×100 mL). The combined organics were washed with water andthen brine before being dried over sodium sulfate, filtered andconcentrated to furnish(S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoicacid (4005 mg, 83% yield) as a colorless viscous oil.

Step 4:(S)-3-(tert-Butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate

To a solution of(S)-2-(tert-butoxycarbonyl)-3-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)propanoicacid (4000 mg, 11857 μmol) in 100 mL of THF at 0° C. was added TEA (1653μl, 11857 μmol) and isobutyl chloroformate (1551 μl, 11857 μmol).Reaction was stirred at 0° C. for 2 hours then filtered through a smallfrit of celite. The filtered solution was cooled to 0° C. and freshlyprepared diazomethane (0.5 M in ether, 35570 μl, 17785 μmol) was added.The reaction solution was maintained at 0° C. for 1 hour then pouredinto saturated sodium bicarbonate 250 mL. The aqueous layer wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water and then brine and dried over Na₂SO₄.Concentration under reduced pressure provided the diazo ketone as ayellow oil that was carried on without further purification. The diazoketone was taken up in 100 mL of THF, cooled to 0° C. and treated withHBr (33 wt % in AcOH) (2147 μl, 11857 μmol). After stirring for 30minutes potassium carbonate (2458 mg, 17785 μmol) and sodium acetate(9726 mg, 118565 μmol) were added and the THF was removed in vacuo. 25mL of DMF was added and the reaction slurry was stirred at rt for 10minutes, then diluted with ethyl acetate (50 mL) and poured into water(100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL)and the combined organic layers were washed with water and then brineand dried over Na₂SO₄. Concentration under reduced pressure andpurification of the crude by silica gel chromatography (Analogix, 120 g)0-25% ethyl acetate in hexanes provided(S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (3560 mg, 76% yield) as a slightly yellow oil.

Step 5:(2S,3S)-3-(tert-Butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate

A solution of(S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (3270 mg, 8311 μmol) in 100 mL of ethanol was cooled to −78° C.and added to a solution of lithium aluminum tri-tert-butoxyhydride(16623 μl, 16623 μmol) in 45 mL of ethanol at −78 C dropwise via acannula over 10 minutes. After stirring at −78° C. for 2 hours thereaction was quenched with 25 mL of 1 N HCl and diluted with ethylacetate (500 mL). The mixture was poured into 200 mL of water, thelayers were separated and the aqueous layer was extracted with ethylacetate (3×100 mL). The combined organics were washed with water, brine,and dried over sodium sulfate and concentrated to provide(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (3220 mg, 98% yield) as a white solid.

Step 6: (4S,5S)-tert-butyl4-((2,2-dimethylbenzo[d][1,3]-dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate

To a solution of(2S,3S)-3-(tert-butoxycarbonyl)-4-(2,2-dimethylbenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (1350 mg, 3414 μmol) in 5 mL of DMF was added2-methoxyprop-1-ene (1961 μl, 20483 μmol) and((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonicacid (397 mg, 1707 μmol). After stirring for 20 hours the reaction waspoured into ice-cold aqueous saturated sodium bicarbonate (150 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with water, brine, and dried over sodium sulfate. The orange oilwas taken up in 30 mL of methanol, cooled to 0° C. and treated withpotassium carbonate (1415 mg, 10242 μmol). The reaction was allowed towarm to rt over the course of 1 hour and stirred for a total of 2 hours.The reaction was diluted with ethyl acetate (25 mL) and poured insaturated ammonium chloride 50 mL. The aqueous layer was extracted withethyl acetate (3×50 mL). The combined organic layers were washed withwater, brine dried over Na₂SO₄, filtered, concentrated under reducedpressure and purification of the resulting crude material by silica gelchromatography provided (4S,5S)-tert-butyl4-((2,2-dimethylbenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateas an orange foam.

Example 6

(4S,5R)-tert-Butyl4-((7-fluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateand (4S,5S)-tert-butyl4-((7-fluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateStep 1: (Z)-Methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)acrylate

To a solution of n-tert-butyloxycarbonyl-a-phosphonoglycine trimethylester (7.85 g, 26.4 mmol) in 50 mL of DCM at 0° C. was added DBU (6.54ml, 43.7 mmol) dropwise over 1 minute. A solution of7-fluorobenzo[d][1,3]dioxole-5-carbaldehyde (7000 mg, 41.6 mmol) in 25mL of DCM was added dropwise over 10 minutes, and the mixture was warmedto rt and stirred for 2 hours. The reaction was diluted with DCM (25 mL)and poured in saturated ammonium chloride (100 mL). The aqueous layerwas extracted with DCM (1×50 mL) and the combined organic layers werewashed with 10% aqueous sodium bicarbonate, then with water, brine anddried over Na₂SO₄. Concentration under reduced pressure to andpurification by silica gel chromatography provided (Z)-methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)acrylate(12.9 g, 91.3%) as a white solid.

Step 2: (S)-Methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]-dioxol-5-yl)propanoate

To a slurry of (Z)-methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)acrylate(8000 mg) in 70 mL of methanol was added [(1S,1S,2R,2R′) [Rh(duanphos)cod]BF₄ (41.64 mg, 58.94 μmol; Strem). The mixture was purgedwith hydrogen 5 times and then sealed at 50 psi of H₂ and stirred for 8hours. Concentration and purification of the reaction crude by silicagel chromatography provided (S)-methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoate(12.0 g, 99.4%) as a colorless oil.

Step 3:(S)-2-(tert-Butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoicacid

To a solution of (S)-methyl2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoate(12000 mg, 35 mmol) in 200 mL of THF at 0° C. was added LiOH (0.2 M)(52735 μl, 52735 μmol) dropwise over 10 minutes. After stirring for 1hour, more LiOH (0.2 M) (17578 μl, 17578 μmol) was added and the mixturewas stirred for another 1 hr. The reaction mixture was washed with ether(2×250 mL), the aqueous layer was acidified with 2N HCl to pH of about 4and extracted with EtOAc (3×300 mL). The combined organics were washedwith water, brine, dried over sodium sulfate, filtered and concentratedto provide(S)-2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoicacid (11.3 g, 98% yield) as a colorless oil.

Step 4:(S)-3-(tert-Butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate

To a solution of(S)-2-(tert-butoxycarbonyl)-3-(7-fluorobenzo[d][1,3]dioxol-5-yl)propanoicacid (11300 mg, 35 mmol) in 400 mL of THF at 0° C. was added TEA (5 ml,35 mmol) and isobutyl carbonochloridate (5 ml, 35 mmol). After stirringfor 75 minutes the reaction was filtered through celite and then cooledto 0° C. at which point freshly prepared diazomethane (0.5 M in ether)(104 ml, 52 mmol) was added. After stirring for 1 hour the reaction waspoured into saturated sodium bicarbonate 500 mL. The aqueous layer wasextracted with ethyl acetate (3×300 mL). The combined organic layerswere washed with water and then brine and dried over Na₂SO₄.Concentration under reduced pressure provided the diazo ketone as ayellow solid that was carried on without further purification. The diazoketone was taken up in 400 mL of THF and cooled to 0° C. at which pointHBr (33% in Acetic acid) (7 ml, 41 mmol) was added over 1 minute. Thereaction was maintained at 0° C. for 15 minutes before potassiumcarbonate (7 g, 52 mmol) and sodium acetate (28 g, 345 mmol) were added.The THF was removed in vacuo and 100 mL of DMF was added. The resultingslurry was allowed to stir for 1 hour at which point the reaction wasdiluted with ethyl acetate (250 mL) and poured in water (300 mL). Theaqueous layer was extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with water and then brine and dried overNa₂SO₄. Concentration of the filtered solvents under reduced pressureprovided(S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (12.5 g, 94% yield) as a yellow oil.

Step 5:(2R,3S)-3-(tert-Butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate and(3S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate

To a slurry of lithium tri-tert-butoxyhydroaluminate (65211 μl, 65211μmol, 1 M in THF) in 100 mL of ethanol at −78° C. was added a slurry of(S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-oxobutylacetate (12500 mg, 32606 μmol) in 300 mL of ethanol cooled to −50 C overthe course of 20 minutes via cannula. The reaction was maintained atbetween −78 and −40 C for 8 hours before being allowed to warm to −25 Cuntil LCMS and TLC showed complete consumption of starting material. Thereaction was then quenched with 300 mL of 1 N HCl. The mixture wasdiluted with ethyl acetate (1000 mL) and 200 mL of water, the layerswere separated and the aqueous layer was extracted with 3×300 mL ofethyl acetate. The combined organic layers were washed with water,brine, and dried over sodium sulfate, filtered and concentrated toprovide a slurry. The slurry was taken up in 500 mL of DCM and washedwith brine, then dried over sodium sulfate, and purified by silica gelto provide an inseparable 4:1 mixture of(2R,3S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate and(2S,3S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (7.25 g, 57%).

Step 6: (4S,5R)-tert-Butyl4-((7-fluorobenzo[d][1,3]-dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylateand (4S,5S)-tert-butyl4-((7-fluorobenzo[d][1,3]dioxol-5-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate

2-Methoxy-1-propene (7.6 ml, 81 mmol) and (+/−)-10-camphorsulfonic acid(1.6 g, 6.7 mmol) were successively added to a solution containing a 4:1mixture of(2R,3S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate and(2S,3S)-3-(tert-butoxycarbonyl)-4-(7-fluorobenzo[d][1,3]dioxol-5-yl)-2-hydroxybutylacetate (5.2 g, 13 mmol) in 50 mL of DMF. The mixture was stirred at rtovernight and another 2 mL of methoxypropene and 200 mg of CSA wereadded to the reaction. After stirring for another 5 hours, the reactionwas diluted with ethyl acetate (100 mL) and poured in saturated sodiumbicarbonate (250 mL). The layers were separated and the aqueous layerwas extracted with ethyl acetate (3×100 mL). The combined organic layerswere washed with water and then brine, dried over Na₂SO₄ and filtered.Concentration of the solvents under reduced pressure provided anacetonide that was used immediately in the next step. The acetonide(5700 mg, 13.4 mmol) was dissolved in 150 mL of MeOH and cooled to 0° C.at which point potassium carbonate (5.55 g, 40.2 mmol) was added. Afterstirring at 0° C. for 2 hours 300 mL of water was added and the organicswere removed in vacuo. The aqueous layer was extracted with ethylacetate (3×200 mL) the combined organic layers were washed with brine,dried and concentrated. Purification of the crude concentrated materialby HPLC provided both title compounds as white solids.

Example 7

tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-cyclopropyl-4-hydroxybutan-2-ylcarbamate

The title compound was obtained using a method analgous to thatdescribed in step 2 of Example 3. MS m/z: 260 (M+1).

Example 8

tert-Butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-1-(3-(difluoromethoxy)-4-fluorophenyl)-4-hydroxybutan-2-ylcarbamate

The title compound was obtained using a method analgous to thatdescribed in steps 1 & 2 of Example 3. MS m/z: 380 (M+1).

Example 9

(4S)-2,2-Spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amineStep 1: 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide

5-(Methoxymethoxy)-2-neopentylpyridine (11.0 g, 52.6 mmol) was dissolvedin CH₂Cl₂ (200 mL) to which mCPBA (18.1 g, 105 mmol) was added, and themixture was stirred under N₂ for about 4 h. The mixture was quenchedwith 1 M NaOH (200 mL) and stirring was continued vigorously for 10 min.The mixture was extracted with CH₂Cl₂ (2×200 mL), the combined organiclayers were washed with saturated NaCl, dried (Na₂SO₄), and evaporatedto give 5-(methoxymethoxy)-2-neopentylpyridine-N-oxide (11.8 g, 99.7%yield) as a brown oil which was used without purification in the nextstep.

Step 2: 3-(methoxymethoxy)-6-neopentylpicolinonitrile

5-(Methoxymethoxy)-2-neopentylpyridine-N-oxide (11.5 g, 51 mmol) wasdissolved in CH₂Cl₂ (50 mL) to which benzoyl chloride (12 ml, 102 mmol)and (trimethylsilyl)formonitrile (14 ml, 102 mmol) were added. Themixture was stirred under N₂ 4 h, quenched with saturated NaHCO₃ (150mL), and extracted with CH₂Cl₂ (3×100 mL). The combined organic layerswere washed with saturated NaHCO₃ (2×50 mL), dried (MgSO₄), andevaporated to give the crude product as a brown oil, which was purifiedby ISCO (330 g SiO₂, O-40% EtOAc/Hexane) to give3-(methoxymethoxy)-6-neopentylpicolinonitrile (8.8 g, 74% yield) as aclear oil.

Step 3: 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone

3-(Methoxymethoxy)-6-neopentylpicolinonitrile (8.3 g, 35 mmol) wasdissolved in THF (125 mL). The solution was cooled to 0° C. andmethylmagnesium chloride (24 ml, 71 mmol) (3.0 M in Et₂O) was added. Thereaction mixture stirred for 2 h at rt under N₂ then quenched withsaturated NH₄Cl (50 mL) and extracted with EtOAc (3×50 mL). The organiclayer was dried over MgSO₄ and evaporated to give the crude product as ayellow oil. Purification of the crude residue by ISCO (40 g SiO₂, O-40%EtOAc/Hexane) gave1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone (3.8 g, 43%yield) as a clear, light orange oil.

Step 4: 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone

A solution of 1-(3-(methoxymethoxy)-6-neopentylpyridin-2-yl)ethanone(3.75 g, 15 mmol) in (2:1:1) 5 M HCl: i-PrOH:THF (100 mL) was stirred 16h at rt. The mixture was concentrated to remove the THF and i-PrOH. Theresulting solution consisting of the product in aqueous HCl was quenchedby slow addition to a solution of saturated aqueous NaHCO₃ (500 mL)containing excess solid NaHCO₃ (28 g). The aqueous layer was extractedwith CH₂Cl₂ (3×100 mL), the organic layers combined and washed withsaturated aqueous NaCl (100 mL), dried (MgSO₄), and concentrated to givethe crude product as a brown oil. The product was purified by ISCO(0-10% EtOAc/Hexanes) to give1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone (1.98 g, 64% yield) as aclear, colorless oil.

Step 5:2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4-one

A mixture of 1-(3-hydroxy-6-neopentylpyridin-2-yl)ethanone (1.90 g, 9167μmol), pyrrolidine (2296 μl, 27501 μmol), and cyclobutanone (2570 mg,36667 μmol) in CH₃CN (20 mL) was heated in a 65° C. oil bath for 3 h.The mixture was cooled to rt, then diluted with EtOAc (25 mL), washedwith H₂O, saturated aqueous NH₄Cl, saturated aqueous NaCl, dried(MgSO₄), and concentrated. Purification of the resulting crude materialby ISCO (40 g SiO₂, 10-20% EtOAc/Hexanes) gave2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4-one(710 mg, 29.9% yield) as a yellow solid.

Step 6:(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol

To a vial containing2,2-spirocyclobutan-6-neopentyl-2,3-dihydropyrano[3,2-b]pyridin-4-one(710 mg, 2738 μmol) was added sodium formate (1862 mg, 27377 μmol) andtetrabutylammonium bromide (26.5 mg, 82.1 μmol). Toluene (5 mL) and H₂O(2.5 mL) were added and the solution purged 3× with N₂, then with an Arballoon for 15 min.[(1R,2R)-2-Amino-1,2-diphenyl-N-(p-tolylsulfonyl)ethylamido]chloro(η⁶-pcymene)ruthenium(II) (53.4 mg, 82.1 μmol) was added and the biphasicreaction was stirred at rt under Ar for 24 h. H₂O (10 mL) was added andthe reaction was extracted with CH₂Cl₂ (3×20 mL). The combined organiclayers were dried (Na₂SO₄), and concentrated to give a brown oil, whichwas purified by ISCO (40 g SiO₂, 5-40% EtOAc/Hexane) gives(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol(460 mg, 64.3% yield) as a clear oil.

Step 7:(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine

To a solution of(4R)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-ol(460 mg, 1760 μmol) in toluene (4 mL) is added diphenylphosphoryl azide(531 μl, 2464 μmol) then 1,8-diazabicyclo(5.4.0)-7-undecene (368 μl,2464 μmol). The reaction mixture was stirred under N₂ at rt 23 h. Theclear, light yellow solution first turned into a brown cloudy/opaquesolution after 30 min. To speed up the reaction rate, the mixture washeated to 40° C. and stirred an additional 5 h. Water (20 mL) was addedand the reaction mixture was extracted with EtOAc (3×20 mL). Thecombined organic layers were dried (Na₂SO₄), and concentrated to givethe crude product as a brown oil, which was purified by ISCO (40 g SiO₂,0-20% EtOAc/Hexane) gives(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine(250 mg, 49.6% yield) as a white solid.

Step 8:(4S)-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine

A solution of(4S)-4-azido-2,2-spirocyclobutan-6-neopentyl-3,4-dihydro-2H-pyrano[3,2-b]pyridine(250 mg, 873 μmol) in methanol (10 mL) was purged with N₂ (3×), thenpalladium (260 mg, 244 μmol) (10 wt % on carbon) was added. The reactionwas purged with H₂ (3×), then stirred at rt under H₂ 1.5 h. Thesuspension was filtered through a pad of Celite, MeOH wash (4×5 mL), andthe solution concentrated to give the crude product (245 mg) as a whiteoily solid, which was purified by ISCO (12 g SiO₂, 0-10% MeOH/CH₂Cl₂) togive the title compound as a white solid.

Example 10

(4S)-6-(1,1-Difluoroethoxy)-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1:(4S)-tert-Butyl-6-acetyl-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl(allyl)carbamate

To a solution of (4S)-tert-butyl6-bromo-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl(allyl)carbamate(8.1 g, 20 mmol) in Et₂O (100 mL) at −78° C. was added tert-butyllithium(23 ml, 40 mmol) over 3 minutes. The reaction was allowed to stir 10min. at −78° C., then acetaldehyde (4.5 ml, 79 mmol) was added, thereaction was then warmed to rt over 30 min, and quenched with NH₄Cl (200mL). The reaction was extracted with EtOAc (3×100 mL), the combinedorganic layers were washed with saturated NaCl (100 mL), dried (Na₂SO₄),and concentrated to give crude product as a dark yellow/orange oil. Thecrude was carried on into the next step without purification. To asolution of the crude product from above in CH₂Cl₂ (50 mL) at 0° C., wasadded sodium bicarbonate (6.64 g, 79.0 mmol) and Dess-Martin periodinane(10.5 g, 24.7 mmol) simultaneously. The ice bath was removed and thereaction was stirred for 2 h at rt, then quenched with saturated Na₂SO₃(300 mL), extracted with CH₂Cl₂ (3×200 mL), concentrated. The crudematerial was purified by ISCO (10-50% EtOAc/Hexane) to give the titlecompound (4.10 g, 55.7% yield over 2 steps) as a clear, light yellowoil.

Step 2:(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)ethanone

To a 150 mL rbf with (4S)-tert-butyl6-acetyl-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl(allyl)carbamate(2.05 g, 5504 μmol) and CH₂Cl₂ (50 mL) was added 2,2,2-trifluoroaceticacid (5089 μl, 66048 μmol). The reaction was allowed to stir at RT for 5h, then diluted with CH₂Cl₂ (50 mL). The mixture was washed withsaturated NaHCO₃ (2×100 mL) and the organic layer degassed with Argonfor 10 minutes. The degassed solution was treated with1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (2.21 g, 14154 μmol) andtetrakistriphenylphosphine palladium(0) (254 mg, 220 μmol) and stirredat rt for 24 hours. The reaction mixture was washed with NaOH (1N, 2×50mL), and HCl (1N, 2×50 mL). The acidic aqueous layer was then basifiedto pH 14 with NaOH (5N, 25 mL) and extracted with DCM (3×50 mL). Thecombined organic layers were dried (Na₂SO₄) and concentrated to give(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)ethanone(810 mg, 63.4%) as a light yellow oil.

Step 3:(4S)-6-(1,1-difluoroethoxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

To a 20 mL polyethylene vial was added(4S)-1-(4-amino-2,2-spirocyclobutan-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)ethanone(410 mg, 1765 μmol) and HF/pyridine (1 mL). Xenon difluoride (359 mg,2118 μmol) was added to the mixture followed by CH₂Cl₂ (1 mL). Thereaction was stirred at rt 24 h, then quenched by slowly adding it tosaturated NaHCO₃ (100 mL) with solid NaHCO₃ (5 g). The mixture wasextracted with CH₂Cl₂ (3×50 mL). The combined organic layers werecollected, dried (Na₂SO₄) and concentrated to give the crude product asa brown oil. The crude was purified by ISCO (2×12 g SiO₂ stacker, 0-8%MeOH/CH₂Cl₂) to give(4S)-6-(1,1-difluoroethoxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineas an orange oil.

Example 11

(1R,2S,4′S)-2-Hydroxy-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amineand(1S,2R,4′S)-2-hydroxy-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amineStep 1: (cis)-1-Allyl-2-(benzyloxy)cyclobutanol and(trans)-1-allyl-2-(benzyloxy)cyclobutanol

To a RBF under argon was added 2-(benzyloxy)cyclobutanone (8.0 g, 45mmol) and THF (100 mL). The reaction was cooled to 0° C. andallylmagnesium bromide (113 ml, 113 mmol) (1.0 M in Et₂O) was added over20 min. The clear colorless solution turned into a tan solution with awhite suspension. The ice bath was removed and the reaction warmed to rtand stirred 7 h. The reaction was quenched by slow addition to saturatedaqueous NH₄Cl (500 mL). The reaction was diluted with EtOAc (300 mL) andextracted. The aqueous layer was extracted with EtOAc (2×250 mL), thecombined organic layers washed with saturated NaCl (250 mL), dried(Na₂SO₄), and concentrated to give a clear, light yellow oil, which waspurified by ISCO (330 g SiO₂, 10-40% EtOAc/Hexane) gives the less polarisomer (cis)-1-allyl-2-(benzyloxy)cyclobutanol (4.0 g, 40% yield)followed by the more polar isomer(trans)-1-allyl-2-(benzyloxy)cyclobutanol (2.4 g, 24% yield) as a clear,colorless oils.

Step 2:((1,2-cis)-1-Allyl-2-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane

(Cis)-1-Allyl-2-(benzyloxy)cyclobutanol (4.00 g, 18.3 mmol) wasdissolved in CH₂Cl₂ (100 mL) to which tert-butyldimethylsilyltrifluoromethanesulfonate (5.05 ml, 22.0 mmol) andN-ethyl-N-isopropylpropan-2-amine (3.99 ml, 22.9 mmol) were added. Thereaction mixture was stirred at rt for 5 h. The reaction was quenchedwith 10% NaCO₃ (300 mL), and the aqueous layer was extracted with CH₂Cl₂(2×100 mL). The combined organic layers were washed with saturated NaCl(50 mL), dried (Na₂SO₄), and concentrated to give a yellow oil, whichwas purified by ISCO (40 g SiO₂, 100% Hexane to give((cis)-1-allyl-2-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane (5.38g, 88.3% yield) as a clear, colorless oil.

Step 3:2-((1,2-cis)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde

((cis)-1-Allyl-2-(benzyloxy)cyclobutoxy)(tert-butyl)dimethylsilane (5.37g, 16 mmol) was dissolved in t-butanol (30 mL, 319 mmol) and H₂O (30 mL)followed by the addition of 4-methylmorpholine n-oxide (3.4 g, 29 mmol)in one portion. After the reactants dissolved, osmium tetroxide (5.1 mL,0.40 mmol) was added and the reaction mixture was stirred at RT for 17h. The reaction mixture was worked up by the addition of 6 g of sodiumsulfite and allowed to stir for 1 h. The reaction mixture was extractedwith ether and the organic phase was concentrated and used directly inthe next step. The crude was dissolved in 1:1 t-BuOH/H₂O (60 mL) andsodium periodate (6.2 g, 29 mmol) was added. The mixture was stirred for3 h. Then H₂O (100 mL) was added and the mixture was extracted with Et₂O(3×100 mL). The combined organic layers were dried (MgSO₄) andconcentrated. The crude was purified by ISCO (120 g SiO₂, 5-20%EtOAc/Hexane to give2-((cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde(4.0 g, 74% yield) as a clear, colorless oil.

Step 4:2-((1,2-cis)-2-(Benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethanol

To a flame-dried 250 mL rbf with 2,2,6,6-tetramethylpiperidine (3.41 ml,20.1 mmol) was added THF (40 mL) and the solution is cooled to −78° C.n-Butyllithium (10.8 ml, 1.60 M, 17.2 mmol) was added dropwise and thereaction was warmed to 0° C. and stirred 5 min. The reaction wasrecooled to −78° C. and 2-fluoro-5-neopentylpyridine (2.40 g, 14.3 mmol)in THF (10 mL) was added and the reaction stirred 45 min at −78° C. Then2-((cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)acetaldehyde(4.00 g, 12.0 mmol) in THF (10 mL) was added dropwise. The reactionmixture was stirred 15 min at −78° C., then quenched by addition ofsaturated NH₄Cl (50 mL), warmed to rt, diluted with H₂O (50 mL) andextracted with Et₂O (3×100 mL). The combined organic layers were washedwith saturated NaCl (100 mL), dried (Na₂SO₄), and concentrated to give acrude product, which was purified by ISCO (120 g SiO₂, 0-20%EtOAc/Hexane) to give the title compound (5.18 g, 86.3%) as a 1:1mixture of diastereomers, as a clear, light yellow oil.

Step 5:(1,2-cis)-2-(Benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2-hydroxyethyl)cyclobutanol

To a flame-dried 100 mL rbf with2-((1,2-cis)-2-(benzyloxy)-1-(tert-butyldimethylsilyloxy)cyclobutyl)-1-(2-fluoro-5-neopentylpyridin-3-yl)ethanol(5.18 g, 10 mmol) was added THF (10 mL) followed by TBAF (12 ml, 1.0 Min THF, 12 mmol). The reaction was stirred at rt for 30 min, thendiluted with H₂O (100 mL) and extracted with Et₂O (3×50 mL). Thecombined organic layers were washed with saturated NaCl (100 mL), dried(Na₂SO₄) and concentrated to give a crude material, which was purifiedby ISCO (120 g SiO₂, 0-20% EtOAc/Hexane) to give(1,2-cis)-2-(benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2-hydroxyethyl)cyclobutanol(3.25 g, 81%) as a 1:1 mixture of diastereomers, a clear, light yellowoil.

Step 6:(1,2-cis)-2-Benzyloxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-12′-pyrano[2,3-b]pyridin-4′-one

To a flame-dried 100 mL rbf with(1,2-cis)-2-(benzyloxy)-1-(2-(2-fluoro-5-neopentylpyridin-3-yl)-2-hydroxyethyl)cyclobutanol(3.06 g, 7.9 mmol) was added THF (500 mL) followed by NaH (1.6 g, 39mmol, 60% in mineral oil). The reaction was heated in a 60° C. oil bathunder N₂ for 4 h, then cooled to rt and quenched with saturated NH₄Cl(200 mL). The aqueous layer was extracted with EtOAc (3×100 mL), and thecombined organic layers dried (MgSO₄) and concentrated to give the crudealcohol, which was used in the next step without purification. The crudematerial was dissolved in CH₂Cl₂ (100 mL) and Dess-Martin periodinane(3.3 g, 7.9 mmol) and sodium bicarbonate (0.66 g, 7.9 mmol) were addedat the same time. The reaction was stirred for 2 h at rt. The reactionwas quenched with saturated aqueous Na₂SO₃ (100 mL), extracted, thenextracted with additional CH₂Cl₂ (2×100 mL). The combined organic layerswere washed with saturated NaCl (100 mL), dried (Na₂SO₄), andconcentrated to give the crude product as a yellow oil. Purification ofthe oil by ISCO (120 g SiO₂, 0-80% EtOAc/Hexane) gave the title compound(2.67 g, 93%) as a clear, light yellow oil.

Step 7: (1R,2S,4′R)-2-Benzyloxy-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-ol

To a stirred solution of (s)-2-methyl-cbs-oxazaborolidine (0.70 ml, 0.70mmol) in THF (10 mL) at 0° C. was added borane-methyl sulfide complex(1.2 ml, 12 mmol) followed by a solution of(1,2-cis)-2-benzyloxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-one(2.57 g, 7.0 mmol) in THF (20 mL) dropwise via syringe pump over about2.8 h. The reaction was stirred an additional 30 min, then was quenchedby dropwise addition (1 drop/10 sec) of 5 M HCl (25 mL) at 0° C. After15 mL HCl was added, bubbling had ceased and the addition rate wasincreased as the ice bath was removed. The reaction was stirred anadditional 2 h at rt. The reaction was recooled to 0° C. and neutralizedwith 5 M NaOH (27 mL). The mixture was then extracted with EtOAc (2×150mL), washed with saturated aqueous NaCl (200 mL), dried (MgSO₄), andconcentrated to give a yellow oil. Purification of the oil by ISCO (120g SiO₂, 20% EtOAc/Hexane) gave a mixture of(1R,2S,4′R)-2-benzyloxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-ol(1.3 g, 50%) and (1S,2R,4′R)-2-benzyloxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-ol(1.3 g, 50%) as a white foam.

Step 9:(1R,2S,4′S)-2-Benzyloxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-12′-pyrano[2,3-b]pyridin-4′-azideand(1S,2R,4′S)-2-benzyloxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-azide

To a solution of (1,2-cis,4′R)-2-benzyloxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-ol(2.6 g, 7.1 mmol) (1:1 mixture of 1,2-spirocyclobutyl diastereomers) intoluene (14 mL) was added diphenylphosphoryl azide (2.1 ml, 9.9 mmol)then 1,8-diazabicyclo(5.4.0)-7-undecene (1.5 ml, 9.9 mmol). The reactionwas stirred under N₂ at rt for 18 h. The clear, light yellow solutionturned into a yellow cloudy/opaque solution after 10 min. Water (100 mL)was added and the reaction mixture extracted with EtOAc (3×200 mL). Thecombined organic layers were washed with saturated NaCl (150 mL), dried(MgSO₄), and concentrated to give the crude product as a brown oil.

To a solution of the brown oil from above in 10:1 THF/H₂O (40 mL) at 0°C. is added NaOH (2.85 ml, 14.3 mmol). After 5 min, trimethylphosphine(2.52 ml, 28.5 mmol) was added dropwise over 4 min. The ice bath wasallowed to melt as the reaction warmed to rt and stirred a total of 18h. The mixture was recooled to 0° C. and 5 N HCl (50 mL) was added. Theresulting mixture was extracted with CH₂Cl₂ (3×100 mL), the combinedorganic layers were washed with 2.5 N HCl (2×50 mL). The combinedaqueous layers were cooled to 0° C. and basified to pH 14 with 5 N NaOH(200 mL). The aqueous layer was extracted with CH₂Cl₂ (3×100 mL) thecombined organic layers dried (Na₂SO₄), and concentrated to give 2.9 gcrude product as a viscous yellow oil. Purification of the oil by ISCO(120 SiO₂, 0-10% MeOH/CH₂Cl₂ gradient elution) gave a 1:1 mixture of thetitle compounds (1.870 g, 71.6% yield) as a yellow oil.

Step 10:(1R,2S,4′S)-2-Hydroxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-12′-pyrano[2,3-b]pyridin-4′-amineand (1S,2R,4′S)-2-hydroxy-6′neopentyl-3′,4′dihydrospirolcyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amine

To a solution of(1,2-cis,4′S)-2-benzyloxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-azide(1.320 g, 3.6 mmol) in MeOH (50 mL) under Ar is added Pd Black (76.7 mg,720 μmol). H₂ gas was bubbled though the suspension for 15 min. Thereaction was then stirred at rt under an atmosphere of H₂ (balloon) for48 h.

After 48 h, the H₂ atmosphere was replaced with N₂, and palladiumhydroxide (506 mg, 720 μmol) was added, the reaction was sparged with H₂and stirred for 24 h at rt. The H₂ atmosphere was replaced with N₂, andthe suspension was filtered through a plug of Celite, washed with MeOH(3×50 mL), and the combined filtrates were concentrated in vacuo to givethe crude product. Purification of the crude material by ISCO (120 gSiO₂, 0-30% MeOH/CH₂Cl₂ gradient elution) gave a mixture of(1R,2S,4′S)-2-hydroxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amine(415 mg, 41.7% yield) and(1S,2R,4′S)-2-hydroxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amineas a yellow solid.

Example 12

(1R,2R,4′S)-2-Hydroxy-6′-neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amineand(1S,2S,4′S)-2-hydroxy-6′neopentyl-3′,4′dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amine

The title compounds were prepared by a method analogous to thatdescribed in Example 11 above, starting with(trans)-1-allyl-2-(benzyloxy)cyclobutanol as the starting material.

Example 13

(S)-3-(4-Amino-8-fluoro-2,2-spirocyclobutylchroman-6-yl)-2,2-dimethylpropanenitrileStep 1: 1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone

4-Bromo-2-fluorophenyl acetate (126 g, 540 mmol) in 1,2-dichlorobenzene(53 mL) was added dropwise to aluminum(III) chloride (72 g, 540 mmol) in1,2-dichlorobenzene (64 mL) with vigorous stirring to give a redsolution. The solution was heated to 120° C. for 60 hours, cooled,diluted with DCM, and added to 1N HCl at 0° C. The layers were separatedand the aqueous layer was extracted with DCM. The combined organiclayers were washed with 1N HCl, water, brine, and dried over sodiumsulfate and concentrated. The crude material was taken up in hexanes andadded to aqueous 1N NaOH at 0° C. The solid was collected and washedwith hexanes. The aqueous filtrate and solid were acidified withconcentrated HCl and extracted with ethyl acetate. The combined organiclayers were washed with water, brine, dried over sodium sulfate, andconcentrated. The crude solid was recrystallized from MeOH to afford thetitle compound (46 g, 37% yield).

Step 2: 6-Bromo-8-fluoro-2,2-spirocyclobutylchroman-4-one

1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone (15.00 g, 64 mmol),pyrrolidine (8 ml, 97 mmol), DIPEA (11 ml, 64 mmol), and cyclobutanone(9 ml, 129 mmol) were heated at 65° C. for 12 hours. After cooling, thereaction was diluted with EtOAc and washed with 1N HCl. The aqueouslayer was extracted with EtOAc. The organic layers were combined, washedwith water, brine, dried over sodium sulfate and concentrated. Theresidue was chromatographed on a silica gel column (10:1 Hexanes/Ether)to afford the title compound (9.73 g, 53% yield) as an orange solid. MSm/z: 285.0 (100%, M).

Step 3: (R)-6-Bromo-8-fluoro-2,2-spirocyclobutylchroman-4-ol

(s)-2-Methyl-CBS-oxazaborolidine, 1M in toluene (3.41 ml, 3.41 mmol) wasadded to a solution of borane-dimethyl sulfide (4.86 ml, 51.2 mmol) in74 mL of toluene at 0° C. After stirring 20 minutes,6-Bromo-8-fluoro-2,2-spirocyclobutyl chroman-4-one (9.73 g, 34.1 mmol)was added via syringe pump in 106 mL of toluene over 1.5 hour at −5° C.After stirring an additional 30 minutes at −50° C. the reaction wasquenched by the addition of methanol and then 1N HCl. The mixture wasextracted with ethyl acetate and the combined organic layers were washed2× with 50% saturated ammonium chloride, brine, and dried over sodiumsulfate. Concentration of the filtered organic layer afforded the titlecompound as yellow oil.

Step 4: (S)-4-Azido-6-bromo-8-fluoro-2,2-spirocyclobutyl chromane

Diphenyl azidophosphate (4.90 ml, 22.7 mmol) was added to a solution of6-Bromo-8-fluoro-2,2-spirocyclobutyl chroman-4-one (4.35 g, 15.2 mmol)and DBU (3.43 ml, 22.7 mmol) in toluene (28 mL). The reaction wasallowed to stir 48 hours and was filtered through a pad of silica geland washed with EtOAc. Concentration of the EtOAc afforded the titlecompound.

Step 5: (S)-6-Bromo-8-fluoro-2,2-spirocyclobutylchroman-4-amine

Raney nickel (2800), slurry, in water (0.4 g, 6 mmol) was added to(S)-4-Azido-6-bromo-8-fluoro-2,2-spirocyclobutyl chromane (4.73 g, 15mmol) dissolved in i-PrOH (150 mL). Hydrazine, monohydrate (5 ml, 76mmol) was added and the reaction mixture was stirred 30 minutes beforebeing filtered through a pad of Celite washing with ethanol. The EtOHsolvent was concentrated, and the resulting crude material was purifiedby silica gel chromatography (20:1 DCM/MeOH (2M NH₃) to afford the titleproduct. MS m/z: 269.0 (100%, M-17).

Step 6: (S)-tert-Butyl6-bromo-8-fluoro-2,2-spirocyclobutylchroman-4-ylcarbamate

(S)-6-Bromo-8-fluoro-2,2-spirocyclobutylchroman-4-amine (3.00 g, 10mmol), TEA (2.2 ml, 16 mmol), and BOC-anhydride (3.0 g, 14 mmol) werestirred in DCM (30 mL) for 12 hrs and concentrated. The crude materialwas taken up in EtOAc and washed with saturated ammonium chloride,water, brine, dried over sodium sulfate and concentrated. The crudematerial was purified by recrystallization from methanol and water toafford the title product as a white solid.

Step 7: (S)-tert-Butylallyl(6-bromo-8-fluoro-2,2-spirocyclobutylchroman-4-yl)carbamate

(S)-tert-Butyl 6-bromo-8-fluoro-2,2-spirocyclobutylchroman-4-ylcarbamate(5.7 g, 15 mmol) was dissolved in DMF (70 mL) and cooled to 0° C. NaH(0.71 g, 18 mmol) was added carefully to the mixture and the solutionwas allowed to stir for 40 minutes. Allyl bromide (1.4 ml, 16 mmol) wasadded and the reaction mixture was stirred 45 minutes and then dilutedwith saturated aqueous ammonium chloride. Water was added and thesolution was extracted with ether. The combined organic layers werewashed with water, brine, dried over magnesium sulfate, filtered andconcentrated to afford the title compound. MS m/z: 370.1 (100%, M-55).

Step 8: (S)-tert-Butylallyl(8-fluoro-6-(hydroxymethyl)-2,2-spirocyclobutylchroman-4-yl)carbamate

(S)-tert-Butylallyl(6-bromo-8-fluoro-2,2-spirocyclobutylchroman-4-yl)carbamate (6.30g, 15 mmol) was dissolved in diethyl ether (75 mL) and cooled to −78° C.tert-butyllithium (1.7 M) (19 ml, 33 mmol) was added dropwise to give adark orange solution. After 20 minutes, DMF (13 ml, 163 mmol) was addedand the solution was stirred for 45 minutes before being quenched by theaddition of saturated ammonium chloride and water. The aqueous solutionwas extracted with EtOAc and the combined organic layers were washedwith water, brine, dried over sodium sulfate and concentrated. The crudematerial was dissolved in 80 mL of MeOH, cooled to 0° C. and NaBH₄ (0.84g, 22 mmol) was added to the cooled mixture. After stirring 40 minutesthe reaction mixture was quenched by addition of saturated ammoniumchloride and water. The aqueous solution was extracted with EtOAc andthe combined organic layers were washed with water, brine, dried oversodium sulfate and concentrated. The crude residue was purified bycolumn chromatography (4:1 Hex/EtOAc) to give the title product.

Step 9: (S)-tert-Butylallyl(6-(2-cyano-2-methylpropyl)-8-fluoro-2,2-spirocyclobutylchroman-4-yl)carbamate

Dibromotriphenylphosphorane (4.28 g, 10.1 mmol) was added to a solutionof (S)-tert-butyl allyl(8-fluoro-6-(hydroxymethyl)-2,2-spirocyclobutylchroman-4-yl)carbamate(3.48 g, 9.22 mmol) and N-ethyl-N-isopropylpropan-2-amine (1.61 ml, 9.22mmol) in DCM (80 mL) at 0° C. After stirring 45 minutes at 0° C. and 30minutes at ambient temperature, the reaction was concentrated and takenup in THF (40 mL). In a separate flask, diisopropylamine (8.21 ml, 58.1mmol) was added to THF (90 mL) and the solution was cooled to −780° C.n-Butyllithium (22.1 ml, 55.3 mmol) was added and the solution wasstirred 20 minutes at 0° C. Isobutyronitrile (4.96 ml, 55.3 mmol) wasadded and the yellow solution was stirred 40 minutes at 0° C. before theintermediate benzyl bromide described above in THF (40 mL) was addeddropwise via addition funnel. The reaction was stirred at 0° C. andafter 1 hour was complete. The reaction was quenched with saturatedammonium chloride and was extracted with EtOAc and the combined organiclayers were washed with water, brine, dried over sodium sulfate andconcentrated. The crude material was purified by silica gelchromatography (1.5:1 Hex/EtOAc) to afford the title product. MS m/z:373.3 (100%, M-55).

Step 10:(S)-3-(4-(Allylamino)-8-fluoro-2,2-spirocyclobutylchroman-6-yl)-2,2-dimethylpropanenitrile

(S)-tert-Butyl allyl(6-(2-cyano-2-methylpropyl)-8-fluoro-2,2-spirocyclobutylchroman-4-yl)carbamate(2.90 g, 6.8 mmol) and TFA (25 ml, 324 mmol) were stirred in DCM (50 mL)for 3 hours and concentrated. The crude product was taken up in DCM and1 N NaOH and separated. The aqueous layer was extracted with DCM and thecombined organic layers were washed with brine and dried over sodiumsulfate. Concentration afforded the title product which was used withoutfurther purification. MS m/z: 329.3 (100%, M+1).

Step 11:(S)-3-(4-Amino-8-fluoro-2,2-spirocyclobutylchroman-6-yl)-2,2-dimethylpropanenitrile

(S)-3-(4-(Allylamino)-8-fluoro-2,2-spirocyclobutylchroman-6-yl)-2,2-dimethylpropanenitrilewas dissolved in degassed (N₂) DCM (40 mL) and 1,3-dimethylbarbituricacid (3.2 g, 20 mmol) was added. After two minutes, Pd(PPh₃)₄ (0.78 g,0.68 mmol) was added and the reaction was stirred at ambient temperaturefor 12 hours. The reaction was diluted with DCM and 10% aqueous sodiumcarbonate and the layers were separated. The aqueous layer was extractedwith DCM and the combined organic layers were washed with brine, driedover sodium sulfate and concentrated. The crude product was purified bysilica gel chromatography (20:1 DCM/MeOH (2M NH₃)) to afford the titleproduct. MS m/z: 289.2 (37%, M+1); 272.2 (100%, M-16).

Example 14

(S)-8-Fluoro-2,2-spirocyclobutyl-6-neopentylchroman-4-yl-amine

To zinc(II) chloride (0.5 M THF) (50.3 ml, 25.1 mmol) was addedneopentylmagnesium chloride (1.0 M ether) (39.6 ml, 39.6 mmol) in asealed tube and stirred 20 minutes.1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.557 g,0.762 mmol) was added followed by(S)-6-bromo-8-fluoro-2,2-spirocyclobutylchroman-4-amine (2.18 g, 7.62mmol) in THF (4 mL). The tube was sealed and heated to 70° C. for 12 h.The reaction was cooled and dilute with EtOAc and aqueous solution of a9:1 saturated ammonium chloride/ammonium hydroxide solution (PH=9) andseparated. The aqueous layer was extracted with EtOAc, and the combinedorganic layers were washed with a 9:1 saturated ammoniumchloride/ammonium hydroxide solution (PH=9), water, brine, dried oversodium sulfate, and concentrated. Purification by silica gelchromatography (40:1 DCM/MeOH 2M NH₃) afforded the title product. MSm/z: 261.2 (100%, M-16).

Example 15

(S)-3-(4-Amino-2,2-spirocyclobutylchoman-6-yl)-2,2-dimethylpropanenitrile

The title compound was prepared according to steps 1-11 of the proceduredescribed in Example 9 above.

Example 16

(S)-8-Fluoro-2,2-tetrahydrospirofuranyl-6-neopentylchroman-4-amine Step1: 6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-one

1-(5-Bromo-3-fluoro-2-hydroxyphenyl)ethanone (0.200 g, 0.858 mmol),dihydrofuran-3(2H)-one (0.222 g, 2.57 mmol), and pyrrolidine (0.142 ml,1.72 mmol) were dissolved in MeCN (0.5 mL) and heated in the microwavefor 20 minutes fixed at 60° C. After cooling, the reaction was dilutedwith EtOAc and washed with 1N HCl. The aqueous layer was extracted withEtOAc. The organic layers were combined, washed with water, brine, driedover sodium sulfate, and concentrated. The crude product was purified bysilica gel chromatography (1:4 EtOAc/hexanes) to afford the titledproducts. MS m/z: 301.0 (100%, M).

Step 2: (R)-6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-ol

(s)-2-Methyl-cbs-oxazaborolidine (0.767 ml, 0.767 mmol) was added to asolution of borane-methyl sulfide complex (1.09 ml, 11.5 mmol) in 16 mLof toluene at 0° C. After stirring 20 minutes,6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-one (2.31 g, 7.67mmol) was added via syringe pump in 23 mL of toluene over 1.5 hour at−5° C. After stirring an additional 30 minutes at −50° C. the reactionwas quenched by the addition of MeOH and then 1N HCl. The mixture wasextracted with ethyl acetate and the combined organic layers were washedtwice with 50% saturated ammonium chloride, brine, and dried over sodiumsulfate. Concentration of the filtered organic layer afforded the titledproduct as a yellow oil.

Step 3: (S)-4-Azido-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman

Diphenylphosphoryl azide (1.93 ml, 8.96 mmol) was added to a solution of(R)-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-ol (1.81 g,5.97 mmol) and DBU (1.35 ml, 8.96 mmol) in toluene (10 mL). The reactionwas allowed to stir 48 hours and was filtered through a pad of silicagel with ethyl acetate. Concentration of the filtered organic layerafforded the titled products which were used without furtherpurification.

Step 4.(S)-6-Bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-yl-amine

Raney nickel (2800, as a slurry in water) (0.19 g, 3.3 mmol) was addedto (S)-4-azido-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman. (1.2g, 3.7 mmol) dissolved in i-PrOH (50 mL). Hydrazine hydrate (1.1 ml, 18mmol) was added and the reaction was stirred 30 minutes and thenfiltered through a pad of celite with ethanol, concentrated, andpurified by silica gel chromatography (20:1 DCM/MeOH—NH3) to afford thetitled products. MS m/z: 302.1 (5%, M); 285.1 (100%, M-17).

Step 5:(S)-8-Fluoro-2,2-tetrahydrospirofuranyl-6-neopentylchroman-4-amine

To zinc chloride, 0.5M solution in THF (31 ml, 15 mmol) was added2,2-dimethylpropylmagnesium chloride, 1.0 M solution in diethyl ether(25 ml, 25 mmol) in a sealed tube and stirred 20 minutes.1,1′-Bis(diphenylphosphino)ferrocene-palladium dichloride (0.2 g, 0.3mmol) was added to the mixture followed by(S)-6-bromo-8-fluoro-2,2-tetrahydrospirofuranylchroman-4-amine (0.932 g,3 mmol) in THF (8 mL). The tube was sealed and heated to 70° C. for 12h. The reaction was cooled and diluted with DCM and an aq. solution of a9:1 saturated ammonium chloride/ammonium hydroxide and the layers wereseparated. The aqueous layer was extracted with DCM, and the combinedorganic layers were washed with a 9:1 saturated ammoniumchloride/ammonium hydroxide solution, water, brine, dried over sodiumsulfate, and concentrated. Purification of the crude concentrate bysilica gel chromatography (20:1 DCM/MeOH—NH3) afforded the titleproducts.

Example 17

(S)-7,7-Spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-amineStep 1: 3-Amino-5,5-spirocyclobutylcyclohex-2-enone

5,5-Spirocyclobutylcyclohexane-1,3-dione (15.2 g, 99.9 mmol), HOAc (5.15ml, 89.9 mmol), and ammonium acetate (15.4 g, 200 mmol) were refluxed inbenzene (250 mL) with a Dean-Stark trap for 5 hrs. After cooling, theproduct was filtered from the reaction mixture and the solid was takenup in EtOAc and washed with saturated sodium bicarbonate, brine, driedover sodium sulfate, and concentrated to afford the title product as ayellow solid.

Step 2: 4,4-Dimethylpentanal

DIBAL-H (1 M Hexanes)(80 ml, 80 mmol) was added to4,4-dimethylpentanenitrile (5.9 g, 53 mmol) in DCM (200 mL) at 0° C.After stirring for 1.5 hrs the reaction was quenched with concentratedHCl and diluted with DCM. The aqueous layer was extracted with DCM andthe combined organic layers were washed with concentrated HCl, water,brine, and dried over sodium sulfate. The organics were filtered andconcentrated to afford the title compound which was used without furtherpurification.

Step 3: (Z)-2-(Ethoxymethylene)-4,4-dimethylpentanal

4,4-Dimethylpentanal (4.20 g, 36.8 mmol, Step 2) in 36 mL of THF wasadded over 4 hours by syringe pump to a solution of sodium methoxide, 25wt. % in methanol (15.1 ml, 66.2 mmol), 15 mL of methanol, and methylformate (166 ml, 2685 mmol). Following the addition, the reaction wasdiluted with benzene (50 mL) and DMF (40 mL). The solvents weredistilled off at 90° C. leaving the DMF and residual benzene.Bromoethane (11.0 ml, 147 mmol) was added and the solution was heated at40° C. for 48 hrs and then cooled. The solution was diluted with water,and the reaction was extracted with ether. The combined organic layerswere washed with water, brine, and dried over magnesium sulfate,filtered and concentrated to afford the title compound.

Step 4: 7,7-Spirocyclobutyl-3-neopentyl-7,8-dihydroquinolin-5(6H)-one

(Z)-2-(Ethoxymethylene)-4,4-dimethylpentanal (5.22 g, 31 mmol) and3-amino-5,5-spirocyclobutylcyclohex-2-enone (4.6 g, 31 mmol) were heatedto 140° C. in propionic acid (30 ml, 399 mmol) for 12 hours. Aftercooling, the reaction was diluted with ethyl acetate and washed 2× with1N NaOH. The aqueous layer was extracted with ethyl acetate and thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated. Purification of the crude by silica gelchromatography (3:1 Hexanes/EtOAc) afforded the titled product (3.1 g,39% yield). MS m/z: 258.2 (100%, M+1).

Step 5:(R)-7,7-Spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ol

(s)-2-Methyl-cbs-oxazaborolidine, 1 M in toluene (1.2 ml, 1.2 mmol) wasadded to a solution of borane-dimethyl sulfide (1.7 ml, 18 mmol) in 26mL of toluene at 0° C. After stirring 20 minutes,7,7-spirocyclobutyl-3-neopentyl-7,8-dihydroquinolin-5(6H)-one (3.10 g,12 mmol) was added to the mixture via syringe pump in 37 mL of tolueneover 1.5 hour at −50° C. After stirring an additional 30 minutes at −5°C. the reaction was quenched by the addition of methanol and then 1NHCl. The mixture was extracted with ethyl acetate and the combinedorganic layers were washed 2 times with 50% saturated ammonium chloride,brine, and dried over sodium sulfate, filtered and concentrated toafford the titled product.

Step 6:(S)-5-Azido-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinoline

Diphenylphosphoryl azide (3.5 ml, 16 mmol) was added to a solution of(R)-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ol (2.8g, 11 mmol) and DBU (2.4 ml, 16 mmol). The reaction was allowed to stir24 hours and was filtered through a pad of silica gel washing andeluting with ethyl acetate. Concentration of the EtOAc afforded thetitled product which was used without further purification.

Step 7:(S)-7,7-Spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-amine

A solution of(S)-5-azido-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinoline(1.21 g, 4 mmol) in ethanol (30 mL) was purged with nitrogen gas.Palladium, 5% on calcium carbonate, poisoned with lead (0.5 ml, 4 mmol)was added and the flask was flushed with a balloon of hydrogen gas. Thereaction was allowed to stir under an atmosphere of hydrogen gas for 4hours. After purging the reaction with nitrogen gas, the reaction wasfiltered through a pad of celite with ethanol. The reaction wasconcentrated and purified by silica gel column (20:1 DCM/MeOH 2N NH₃) toafford the titled product. MS m/z: 259.3 (100%, M+1).

Example 18

(S)-8,8-Difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-amineStep 1: (S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate

(S)-7,7-Spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-amine(3.47 g, 13.4 mmol), TEA (2.81 ml, 20.1 mmol), and di-tert-butyldicarbonate (2.93 g, 13.4 mmol) were stirred in DCM (60 mL) for 12 hrsand concentrated. The crude material was taken up in ethyl acetate andwashed with saturated ammonium chloride, water, brine, dried over sodiumsulfate, and concentrated. The crude material was purified bycolumn:chromotography (10:1 to 1:1 Hexanes/EtOAc) to afford the titledproduct.

Step 2: N-oxide of (S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate

m-Chloroperbenzoic acid (0.662 g, 2.30 mmol) was added to a solution of(S)-tert-butyl7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate(0.688 g, 1.92 mmol) in DCM (20 mL) and the solution was stirred 12 hrsbefore being diluted with aqueous saturated sodium bicarbonate andaqueous sodium thiosulfate. The mixture was stirred vigorously for 1.5hrs then separated. The aqueous layer was extracted with DCM and thecombined organic layers were washed with aqueous sodium thiosulfate, 10%sodium carbonate, water, brine, and dried over sodium sulfate. Theorganic layer was filtered and concentrated to afford the title product.

Step 3: (S)-tert-Butyl8-hydroxy-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate

The N-oxide from above (0.719 g, 1.92 mmol, Step 2) was dissolved in DCM(9 mL). Trifluoroacetic anhydride (1.33 ml, 9.60 mmol) was added and thereaction was refluxed for 2 hours and concentrated. The crude productwas dissolved in THF (4.5 mL) and aqueous saturated sodium bicarbonatewas added by pipette in dropwise fashion until no further bubbling wasobserved. The reaction was diluted with ethyl acetate and water and thelayers were separated. The aqueous layer was extracted with ethylacetate and the combined organic layers were washed with water, brine,and dried over sodium sulfate, filtered and concentrated. The crudeproduct was purified by silica gel chromatography (25:1 DCM/MeOH) toafford the titled product. MS m/z: 375.3 (100%, M+1).

Step 4: (S)-tert-Butyl7,7-spirocyclobutyl-3-neopentyl-8-oxo-5,6,7,8-tetrahydroquinolin-5-ylcarbamate

(S)-tert-Butyl8-hydroxy-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate(0.285 g, 0.761 mmol) and Dess-Martin Periodinane (0.968 g, 2.28 mmol)were stirred 12 hrs in DCM (7 mL). The reaction was diluted with etherand aqueous sodium thiosulfate and saturated aqueous sodium bicarbonateand stirred vigorously. The layers were separated and the aqueous layerswere extracted with ether and the combined organic layers were washedwith saturated aqueous sodium bicarbonate and water and concentrated.The residue was taken up in ethyl acetate and washed with brine, driedover sodium sulfate, and concentrated. Purification by silica gelchromatography (1:1 Hexanes/EtOAc) afforded the titled product. MS m/z:373.3 (100%, M+1).

Step 5: (S)-tert-Butyl8,8-difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate

(S)-tert-Butyl7,7-spirocyclobutyl-3-neopentyl-8-oxo-5,6,7,8-tetrahydroquinolin-5-ylcarbamate(0.183 g, 0.491 mmol) was dissolved in DCM (1.5 mL) and cooled to −780°C. DAST (0.130 ml, 0.983 mmol) was added and the reaction mixture wasallowed to warm to RT over 12 hrs and stirred for four additional days.The reaction was diluted with DCM and aqueous 10% sodium carbonate andseparated. The aqueous layer was extracted with DCM and the combinedorganic layers were washed with water, brine, and dried over sodiumsulfate. Concentration of the filtered organic solvent afforded thetitled product. MS m/z: 395.2 (100%, M+1).

Step 6:(S)-8,8-Difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-amine

(S)-tert-Butyl8,8-difluoro-7,7-spirocyclobutyl-3-neopentyl-5,6,7,8-tetrahydroquinolin-5-ylcarbamate(0.194 g, 0.49 mmol) was stirred in a 2:1 solution of DCM and TFA (4.5mL) for 3 hours and concentrated. The crude product was taken up inchloroform and 1N aq. NaOH and the layers were separated. The aqueouslayer was extracted with chloroform and the combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentrated.The crude product was purified by silica gel:chromatography (30:1DCM/MeOH—NH₃) to afford the titled product. MS m/z: 295.2 (100%, M+1).

Example 19

(S)-2,2-Spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1: (1 s,5s)-9-(3,3,3-Trifluoropropyl)-9-bora-bicyclo[3.3.11]nonane

3,3,3-Trifluoroprop-1-ene (2.9 g, 30 mmol) was condensed with a coldfinger and the liquid was allowed to drop into a 500 mL RBF containing9-BBN, 0.5M in THF (58 ml, 29 mmol) cooled in a dry ice/iPrOH bath.After the addition was complete the solution was allowed to stir underN₂ and slowly warm to RT.

Step 2: (S)-tert-butyl2,2-spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

To a 500 mL RBF containing(1s,5s)-9-(3,3,3-trifluoropropyl)-9-bora-bicyclo[3.3.1]nonane (6.3 g, 29mmol, step 1) in THF (58 mL) was added, toluene:EtOH (110 mL, 10:1),(S)-tert-butyl6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(5.12 g, 14 mmol), sodium carbonate, 10% aqueous (28.0 ml, 26 mmol), andpalladium tetrakis (790 mg, 0.68 mmol, Strem). The solution was stirredat 80° C. After 16 hours, LC-MS shows reaction to be ˜20% complete andnot progressing. The reaction was concentrated to half volume and thelayers separated and the aqueous layer extracted with EtOAc (2×30 mL).The combined organic layers were concentrated in vacuo and adsorbed ontoa plug of silica gel and chromatographed through a Redi-Sep® pre-packedsilica gel column (120 g), eluting with 0% to 20% EtOAc in hexane, toprovide (S)-tert-butyl2,2-spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.01 g, 19% yield, 56% brsm) as a yellow oil that began to solidifyupon standing under vacuum overnight.

Step 3:(S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

To a 250 mL round bottomed flask containing (S)-tert-butyl2,2-spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.00 g, 2588 μmol) in EtOAc (40 mL) was added HCl (4M in dioxane, 5mL). The solution was stirred at RT. After 4 hours, another 5 mL of HClwas added to the mixture. After a further 16 hours, the reaction waspoured into sat'd NaHCO₃. The aqueous layer was extracted with EtOAc andthe combined organic layers washed with brine, dried over MgSO₄, andconcentrated in vacuo to give(S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoropropyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine(700 mg, 94.5% yield), as a yellow oil. MS m/z: 287.2 (M+1).

Example 20

(S)-tert-Butyl6-allyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateStep 1: (S)-tert-Butyl6-allyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

A solution of tris(dibenzylideneacetone)dipalladium (0) (0.186 g, 0.203mmol), tri-t-butylphosphonium tetrafluoroborate (0.354 g, 1.22 mmol),cesium fluoride (3.09 g, 20.3 mmol), and (S)-tert-butyl6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.500 g, 4.06 mmol) in dioxane (12 mL) was thoroughly degassed thentreated with allyltributylstannane (6.23 ml, 20.3 mmol). The reactionmixture was heated to 100° C. and allowed to stir 4 hours. The reactionmixture was then diluted with EtOAc, washed with saturated KF solution,water, and brine. The organic layer was dried over MgSO₄ andconcentrated under reduced pressure. Purification of the crude residueby column chromatography gave (S)-tert-butyl6-allyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.820 g, 61.1% yield) as a light yellow solid.

Step 2: (S)-tert-Butyl6-(cyclopropylmethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

A solution of (S)-tert-butyl6-allyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.710 g, 2 mmol) in DCM (1.5 mL) was cooled to −10° C. and treated withdiethylzinc 1M in hexanes (21 ml, 21 mmol), followed by dropwiseaddition of chloroiodomethane (3 ml, 43 mmol). After 1 hour anadditional portion of diethylzinc and chloroiodomethane was added. Afteran additional hour at RT the reaction mixture was quenched withconcentrated NH₄Cl solution and diluted with ether. The organic layerwas washed with 2N NaOH, brine, dried over Na₂SO₄ and concentrated underreduced pressure. The crude residue was retreated with the reaction andwork-up conditions three times. Purification of the crude residue bycolumn chromatography gave (S)-tert-butyl6-(cyclopropylmethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.300 g, 41% yield) as a clear oily solid with minor impurities.

Step 3:(S)-6-(Cyclopropylmethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

A solution of (S)-tert-Butyl6-(cyclopropylmethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.300 g, 0.87 mmol) and DIEA (0.30 ml, 1.7 mmol) in DCM (2 mL) wastreated with trimethylsilyltriflate (0.19 ml, 1.0 mmol) and was allowedto stir at RT overnight. An additional 4 equivalents of DIEA then 4equivalents of trimethylsilyltriflate were then added. After anadditional 2 hours of stirring the reaction mixture was quenched with 4NHCl in dioxane and allowed to stir for 1 hr. The reaction mixture wasdiluted with EtOAc, washed with 2N NaOH, water, and brine. The organicswere dried over MgSO₄ and concentrated under reduced pressure.Purification of the crude residue by column chromatography gave(S)-6-(cyclopropylmethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineas a 2:1 mixture an impurity. This material was used without furtherpurification.

Example 21

tert-Butyl(S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateStep 1: tert-butyl(S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

A solution of tert-butyldimethyl(2-methylallyloxy)silane (9 g, 47 mmol)and 9-BBN 0.5M in THF (95 ml, 47 mmol) was degassed and allowed to stirat RT for 3 hours. A separate solution of palladium(II) acetate (0.2 g,0.9 mmol) and S-Phos (1 g, 3 mmol) in THF (5 mL) and benzene (5 mL) wasthoroughly degassed and allowed to stir at RT for one hour. Thepalladium solution was then added to the borane solution, followed bypotassium phosphate (8 g, 38 mmol) and a solution of (S)-tert-butyl6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate((3.5 g, 9 mmol) in DMF(15 mL). The reaction mixture was degassed andheated to 100° C. 4 hours. Cesium fluoride (14 g, 95 mmol) was addedfollowed by 1 mL water and the reaction mixture was heated to 100° C.overnight. The reaction mixture was decanted to a clean flask andconcentrated. The crude residue was treated with TBAF 1M in THF (19 ml,19 mmol) and was allowed to stir at RT for 2 hours. The reaction mixturewas diluted with EtOAc, washed with saturated NH4Cl solution, water, andbrine. The organics were dried over MgSO₄ and concentrated under reducedpressure. Purification of the crude residue by column chromatographygave tert-butyl(S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.444 g, 42% yield) as a yellow solid.

Step 2: tert-Butyl(S)-6-(2-methyl-3-oxopropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

A solution of tert-butyl(S)-6-(3-hydroxy-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(2.290 g, 6.32 mmol) in wet DCM (20 mL) was treated with Dess-Martinperiodinane (3.22 g, 7.58 mmol) and allowed to stir for 2 hours. Thereaction mixture was diluted with 20 mL ether, treated with 1 mLsaturated NaHCO₃ solution followed by sodium thiosulfate (4.99 g, 31.6mmol) and was allowed to stir at RT for 1 hr. The reaction mixture wasthen diluted with EtOAc, washed with saturated NaHCO₃ solution, water,and brine. The organic layer was dried over MgSO₄ and concentrated underreduced pressure. Purification of the crude residue by columnchromatography gave tert-butyl(S)-6-(2-methyl-3-oxopropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.43 g, 62.8% yield) as a sticky white solid.

Step 3: tert-Butyl(S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

A solution of tert-butyl(S)-6-(2-methyl-3-oxopropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.180 g, 3.27 mmol) in DCM (30 mL) was cooled to −78° C. and treatedwith deoxofluor (0.905 ml, 4.91 mmol). The solution was allowed to warmto RT and triethylamine trihydrofluoride (0.0534 ml, 0.327 mmol) wasadded. After 1.5 hours, so an additional equivalent of deoxofluor wasadded, and the reaction mixture was allowed to stir at RT for anadditional hour. The reaction mixture was concentrated under reducedpressure, and the crude residue was purified by column chromatographyyielding tert-butyl(S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.940 g, 75.1% yield) as a white solid.

Step 4:(4S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

A solution of tert-butyl(S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.015 g, 2.65 mmol) in DCM (10 mL) was treated with TFA (10.2 ml, 133mmol) and allowed to stir overnight at RT. The reaction mixture was thenconcentrated under reduced pressure. The crude residue was dissolved inEtOAc, washed with 1N NaOH and brine. The organics were dried over MgSO₄and concentrated under reduced pressure yielding(4S)-6-(3,3-difluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine(0.720 g, 96.1% yield). The product was a mixture of diastereomers thatwas separted by chiral HPLC and the resulting single isomers were usedfor preparing compounds of Formulas I and II.

Example 22

(1S,3S,4′S)-3-Hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-amineStep 1: (1S,3S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospirolcyclobutane-12′-pyrano[2,3-c]pyridin-4′-one; and(1S,3R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-one

3-(tert-Butyldimethylsilyloxy)cyclobutanone (15 g, 77 mmol),1-(3-Hydroxypyridin-4-yl)ethanone (Example 37, 10.5 g, 77 mmol) andpyrrolidine (19 ml, 230 mmol) were dissolved in 500 ml CH₃CN and stirredat 65° C. for 2 h. TLC analysis revealed the disappearance of the SM andthe formation of a single new spot. The mixture was evaporated (100 mlresidue) and partitioned between water and EtOAc. The phases wereseparated and the aqueous was extracted 3× with EtOAc. The combinedorganic extracts were dried over MgSO₄ and evaporated and the mixturewas purified via glass col. chromatography. The title compounds (8.500g, 35% yield) were obtained as a yellow solid (1:1 mixture of stereoisomers)

Step 2:(1S,3S,4′R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-12′-pyrano[2,3-c]pyridin-4′-ol;(1S,3R,4′R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-ol

(1S,3S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-oneand(1S,3R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-one(1:1 mixture of stereo isomers) (8.5000 g, 26.61 mmol) were dissolved in150 ml toluene and 50 ml water was added. Ar gas was bubbled through themixture for 15 min. Tetrabutylammonium bromide (0.2573 g, 0.7982 mmol),sodium formate (18.09 g, 266.1 mmol) and TPAP (0.5190 g, 0.7982 mmol)were added and the mixture was stirred for 14 h under an Ar atmosphere.The mixture was partitioned between EtOAc and water and the phases wereseparated. The aqueous was extracted 3 times with EtOAc, dried overMgSO₄ and evaporated. Glass col. chrom (10-50% EtOAc in hex.) providedthe title compounds (6.630 g, 77.51% yield) as yellow oil. (1:1 mixtureof stereo isomers). MS m/z: 322.2 (M+1).

Step 3:(1S,3S,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-12′-pyrano[2,3-c]pyridin-4′-azide,(1S,3R,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-azide

(1S,3S,4′R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-ol,(1S,3R,4′R)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-ol(1:1 mixture of stereo isomers) (6.6300 g, 20.62 mmol), diphenylazidophosphate (6.667 ml, 30.93 mmol) and DBU (4.626 ml, 30.93 mmol)were dissolved in 40 ml CH₂Cl₂ and stirred over the weekend. Monitoringrevealed that the starting materials were almost consumed and productformed, but still a large portion of the phosphonate ester remained. 40ml of Water was added and the mixture was extracted 3 times with Et₂O,dried over MgSO₄ and evaporated. The crude product was used w/opurification in the next step. MS m/z: 347.2 (M+1).

Step 4:(1S,3S,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-12′-pyrano[2,3-c]pyridin-4′-amine;(1S,3R,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-amine

The crude(1S,3S,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-azideand(1S,3R,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-azide(1:1 mixture of stereo isomers) from the previous reaction (6.9 g, 20mmol) was dissolved in 200 ml THF and lithium aluminum hydride, 2M inTHF (30 ml, 60 mmol) was added at 0° C. The mixture was stirred for 60min and hydrolyzed with Na₂SO₄-10H₂O until gas evolution had ceased. Themixture was filtered and evaporated and purified. (2-10% MeOH in CH₂Cl₂)glass col. chromatography provided the title compounds) as a yellow oilas a mixture of diastereomers. The diastereomers were separated by SFC.(1S,3S,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-amine(1.200 g, 19% yield) and(1S,3R,4′S)-3-tert-Butyldimethylsiloxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′-aminewere obtained. MS m/z: 321.2 (M+1).

Example 23

(1S,3S,4′S)-6′-(2,2-Dimethylpropyl)-3-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amineStep 1: (1S,3R,4′S)-tert-butyl6′-(2,2-Dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-carbamate

(1S,3R,4′S)-6′-(2,2-Dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amine;(1S,3S,4′S)-6′-(2,2-Dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-amine(mixture of stereoisomers) (7.5000 g, 21.472 mmol) was dissolved in 400ml THF/H₂O (1:1) and carbonic acid monosodium salt (9.0189 g, 107.36mmol) and di-tert-butylpyrocarbonate (9.3723 g, 42.944 mmol) were added.The mixture was stirred over night and 300 ml H₂O was added and theproduct was extracted out with EtOAc (3×800 ml). The combined organicphases were dried over MgSO₄ and evaporated and purified by chiralpurification (SFC). MS m/z: 377.3 (M+1).

Alternatively, (1S,3S,4′S)-tert-butyl6′-(2,2-Dimethylpropyl)-3-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-carbamatecan be made by:(1S,3R,4′S)-6′-(2,2-Dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4′-(BOC)-amine(1.050 g, 2.789 mmol) was dissolved in 13 ml CH₂Cl₂ and DAST (0.4790 ml,3.626 mmol) was added. The reaction was heated to 45° C. for 4 h andcooled to RT. The mixture was poured into 15 ml of sat. NaHCO₃ andextracted 3× with EtOAc (3×150 ml). The combined organic extracts weredried over MgSO4 and evaporated. The crude product was used withoutpurification in the next step. MS m/z: 379.2 (M+1).

Step 2: (1S,3S,4′S)-6′-(2,2-Dimethylpropyl)-3-fluoro-3′,4′-dihydrospiro[cyclobutane-12′-pyrano[2,3-b]pyridin-4′-amine

The crude product from step 1 was dissolved in 5 ml MeOH and treatedwith 20 ml 4M HCl in dioxane. The mixture was stirred for 4 h at RT. andevaporated. The messy mixture was purified on HPLC. The combined HPLCfractions were basified (10% Na2CO3, aq.) and extracted with EtOAc(3×250 ml). The title compound (0.180 g) was obtained as a yellow solid,MS m/z: 279.2 (M+1).

Example 24

(4′S)-6′-(2-Fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin-4′amineStep 1: 1-(5-(methoxymethoxy)pyridin-2-yl)-2-methyl]propan-2-ol

5-(Methoxymethoxy)-2-methylpyridine (22.1500 g, 144.6 mmol) wasdissolved in 1500 ml THF and cooled to −78° C. tert-Butyllithium (97.82ml, 166.3 mmol) was added and the mixture was stirred for 15 min.Acetone, (42.52 ml, 578.4 mmol) was added and stirring of the mixturewas continued for 15 min. The reaction was hydrolyzed with 300 ml H₂Oand extracted with 4 L EtOAc (2×). The combined organic extracts weredried over MgSO₄ and evaporated. Glas col. chrom (20-100% EtOAc providedthe 2 products: 1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol(7.5000 g, 24.55% yield) and2-(5-(methoxymethoxy)-2-methylpyridin-4-yl)propan-2-ol (15.00 g, 49.10%yield). MS m/z: 212.0 (M+1).

Step 2: 2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine

1-(5-(methoxymethoxy)pyridin-2-yl)-2-methylpropan-2-ol (7.600 g, 36.0mmol) was dissolved in 200 ml CH₂Cl₂ and cooled to −78° C. DAST (9.51ml, 72.0 mmol) was added drop wise to the solution and stirring wascontinued for 30 min The mixture was allowed to warm up to 0° C. and washydrolyzed with NaHCO₃ (200 ml). Stirring was continued in the colduntil gas evolution had ceased and the phases were separated.

The aqueous was extracted 2× with EtOAc and the combined organic layerswere dried over MgSO₄ and evaporated. Glass col. Chromatography of thecrude material provided2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.80 g, 75.6%yield) as a pale yellow oil.

Step 3:1-(2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridin-4-yl)ethanol

2,2,6,6-Tetramethylpiperidine (8.26 ml, 49.0 mmol) was dissolved with270 ml THF and 1-butyllithium (14.1 ml, 35.4 mmol) was added at −78° C.The mixture was stirred for 10 min in an ice bath and cooled back to−78° C. A solution of2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridine (5.8000 g, 27.2mmol) in 20 ml THF was added dropwise and the reaction was stirred for20 min. Acetylaldehyde (7.65 ml, 136 mmol) was added to the dark redsolution and the color disappeared. Stirring was continued for 20 minand the mixture was hydrolyzed with 50 ml of water. The mixture waswarmed to RT and extracted 3× with CH₂Cl₂ (300 ml each). The combinedorganic extracts were dried over MgSO₄ and evaporated and purified viaglass col. chrom. (30-80% EtOAc in hex.) to provide1-(2-(2-fluoro-2-methylpropyl)-5-(methoxymethoxy)pyridin-4-yl)ethanol awhite solid. MS m/z: 258.2 (M+1).

Example 25

(4S)-6-(2,2-Difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1: (4S)-tert-Butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

Anhydrous, de-gassed THF (20 mL) was added to2-(dicyclohexylphosphino)-2′-methylbiphenyl (1.2 g, 3.2 mmol) andtris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g, 1.4mmol), and the resulting solution was warmed to 450° C. and sparged withN₂. After 20 min, the reaction mixture was allowed to cool to RT, thenadded to a stirring, degassed mixture of (S)-tert-butyl6-bromo-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(10 g, 27 mmol), finely ground potassium phosphate tribasic (14 g, 68mmol), and acetone (100 mL, 1400 mmol) at RT, and the resulting mixturewas sparged with N₂. After 20 min, the reaction mixture was heated atreflux for 24 h. The reaction mixture was allowed to cool to RT,filtered through a 0.45 μm Teflon filter, and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (gradient elution; 1:1→2:1 ethyl acetate-hexane) to afford 3.7 g(39%) of (S)-tert-butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateas a yellow solid.

Step 2: (4S)-tert-Butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

Diethylaminosulfurtrifluoride (13 mL, 110 mmol) was added to a stirringsolution of (S)-tert-butyl6-(2-oxopropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(3.7 g, 11 mmol), ethanol (0.12 mL, 2.2 mmol), and CH₂Cl₂ (55 mL) at RT.After 24 h, the reaction mixture was added to a rapidly stirringsolution of aqueous 10% Na₂CO₃. After 1 h, ethyl acetate was added, thelayers were separated, the organic material was washed sequentially withaqueous 10% Na₂CO₃ and brine, dried (Na₂SO₄), filtered, and the filtratewas concentrated. The residue was purified by flash chromatography onsilica gel (49:1 CH₂Cl₂-methanol) to afford 1.8 g (46%) of(S)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateas a yellow solid.

Step 3:(S)-6-(2,2-Difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

Hydrogen chloride (12 mL of a 4.0 M solution with 1,4-dioxane, 49 mmol)was added to a stirring solution of (4)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(1.8 g, 4.9 mmol) and CH₂Cl₂ (49 mL) at RT. After 24 h, the reactionmixture was concentrated, the residue was partitioned between aqueous10% Na₂CO₃ and EtOAc, the layers were separated. The organic layer waswashed with aqueous 10% Na₂CO₃, brine, dried (Na₂SO₄), filtered, and thefiltrate was concentrated to afford(S)-6-(2,2-difluoropropyl)-2,2-cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineas a yellow oil.

Example 26

(S)-6-(2,2-Difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1: 1-(6-Fluoropyridin-3-yl)propan-2-one

Anhydrous, de-gassed THF (20 mL) was added to2-(dicyclohexylphosphino)-2′-methylbiphenyl (1.2 g, 3.2 mmol) andtris(dibenzylideneacetone)dipalladium (0) chloroform adduct (1.4 g, 1.4mmol), and the resulting solution was warmed to 450° C. and sparged withN₂. After 20 min, the reaction mixture was allowed to cool to RT, thenadded to a stirring, degassed mixture of 5-bromo-2-fluoropyridine (4.8g, 27 mmol), finely ground potassium phosphate tribasic (14 g, 68 mmol),and acetone (100 mL, 1400 mmol) at RT, and the resulting mixture wassparged with N₂. After 20 min, the reaction mixture was heated at refluxfor 24 h, the reaction mixture was allowed to cool to room temperature,filtered through a 0.45 μm Teflon filter, and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (gradient elution; 4:1→2:1 hexane-ethyl acetate) to give 2.3 g (55%)of 1-(6-fluoropyridin-3-yl)propan-2-one as a brown oil.

Step 2: 5-(2,2-Difluoropropyl)-2-fluoropyridine

Diethylaminosulfurtrifluoride (9.8 mL, 75 mmol) was added to a stirringsolution of 1-(6-fluoropyridin-3-yl)propan-2-one (2.3 g, 15 mmol),ethanol (0.18 mL, 3.0 mmol), and CH₂Cl₂ (60 mL) at RT. After 24 h, thereaction mixture was added to a rapidly stirring solution of aqueous 10%Na₂CO₃. After 1 h, ethyl acetate was added, the layers were separated,the organic layer was washed sequentially with aqueous 10% Na₂CO₃ andbrine, dried (Na₂SO₄), filtered, and the filtrate was concentrated. Theresidue was purified by flash chromatography on silica gel (9:1hexane-ethyl acetate) to afford 1.5 g (57%) of5-(2,2-difluoropropyl)-2-fluoropyridine as a yellow-orange oil.

Step 3:(4S)-2-(1,3-Bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-difluoropropyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl)amine

Butyllithium (4.1 mL of a 2.5 M solution with toluene, 10 mmol) wasadded to a stirring solution of 2,2,6,6-tetramethylpiperidine (2.0 mL,12 mmol) and THF (43 mL) at −78° C. After 5 min, the reaction mixturewas raised above the cooling bath for 10 min, re-cooled to −78° C., andthen a solution of 5-(2,2-difluoropropyl)-2-fluoropyridine (1.5 g, 8.6mmol) and THF (8.6 mL) was added. After 30 min, a solution of2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)acetaldehyde(R)-tert-butylsulfinylimine (4.4 g, 9.4 mmol) and THF (9.4 mL) wasadded. After 20 min, saturated aqueous NaHCO₃ was added, the reactionmixture was allowed to warm to RT, partitioned between saturated aqueousNaHCO₃ and ethyl acetate, the layers were separated, the organic layerwas washed with saturated aqueous NaHCO₃, brine, dried (NaSO₄),filtered, and the filtrate was concentrated. The residue was purified byflash chromatography on silica gel (gradient elution; 4:1→3:1→2:1hexane-ethyl acetate) to afford 2.9 g (53%) of(4S)-2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-difluoropropyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl)amineas a yellow solid.

Step 4:(S)-6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineand(S)-6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

Hydrogen fluoride (24 mL of a 70 wt % solution with pyridine, 1300 mmol)was added to(S)-2-(1,3-bis(tert-butyldimethylsiloxy)cyclobutyl)-1-(5-(2,2-difluoropropyl)-2-fluoropyridin-3-yl)-ethyl-((R)-tert-butylsulfinyl)amine (1.7 g, 2.7 mmol) in Teflon™ reaction vessel, and the reactionmixture was heated at 80° C. After 48 h, the reaction mixture was addedto aqueous 10% Na₂CO₃, the mixture was stirred vigorously for 2 h, ethylacetate was added, the layers were separated, the organic material waswashed with aqueous 10% Na₂CO₃, brine, dried (Na₂SO₄), filtered, and thefiltrate was concentrated to afford 0.64 g (84%) of a mixture of(S)-6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineand(S)-6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineas a yellow solid.

Step 5: (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateand (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

Di-tert-butyl dicarbonate (0.64 g, 2.9 mmol) was added to a stirringsolution of the(S)-6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineand(S)-6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-aminemixture (0.64 g, 2.3 mmol), CH₂Cl₂ (23 mL), and diisopropyethylamine(2.0 mL, 11 mmol) at RT. After 24 h, aqueous 10% Na₂CO₃ was added, themixture was stirred vigorously for 1 h, EtOAc was added, the layers wereseparated, the organic layer was washed with aqueous 10% Na₂CO₃, brine,dried (Na₂SO₄), filtered, and the filtrate was concentrated. The residuewas purified by flash chromatography on silica gel (19:1CH₂Cl₂-methanol) to afford 0.32 g (37%) of a mixture of (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateand (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateas a yellow-brown solid.

Step 6: (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2′-one-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

Dess-Martin periodinane (0.49 g, 1.2 mmol) was added to a mixture of(S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((R)-2′-hydroxy)cyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateand (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-((S)-2′-hydroxycyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.32 g, 0.83 mmol), CH₂Cl₂ (8.3 mL), and NaHCO₃ (0.21 g, 2.5 mmol) atRT. After 2 h, the reaction mixture was purified by flash chromatographyon silica gel (1:1 hexane-ethyl acetate) to afford 0.24 g (75%) of(S)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2′-one-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateas a colorless solid.

Step 7: (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate

Diethylaminosulfur trifluoride (0.41 mL, 3.1 mmol) was added to astirring solution of (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-cyclobutan-2′-one-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate(0.24 g, 0.63 mmol), CH₂Cl₂ (6.3 mL), and ethanol (7.3 L, 0.13 mmol) atRT. After 24 h, the reaction mixture was added to a stirring solution ofaqueous 10% Na₂CO₃, the mixture was stirred for 1 h, partitioned betweenEtOAc and aqueous 10% Na₂CO₃, the layers were separated, the organiclayer was washed with aqueous 10% Na₂CO₃, brine, dried (Na₂SO₄),filtered, and the filtrate was concentrated. The residue was purified byflash chromatography on silica gel (2:1 hexane-ethyl acetate) to give0.15 g (59%) of (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamateas a colorless solid.

Step 8:(4S)-6-(2,2-difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

Hydrogen chloride (0.93 mL of a 4.0 M solution with 1,4-dioxane, 3.7mmol) was added to a stirring solution of (S)-tert-butyl6-(2,2-difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylcarbamate (0.15 g, 0.37 mmol)and CH₂Cl₂ (3.7 mL) at RT. After 24 h, the reaction mixture wasconcentrated, the residue was partitioned between aqueous 10% Na₂CO₃ andethyl acetate, the layers were separated, the organic material waswashed with aqueous 10% Na₂CO₃, brine, dried (Na₂SO₄), filtered, and thefiltrate was concentrated to afford(S)-6-(2,2-difluoropropyl)-2,2-(2′,2′-difluorocyclobutyl)-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineas a yellow solid.

Example 27

(4S)-2,2-Spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amineStep 1: tert-Butylallyl((S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoro-1-hydroxy-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a cooled (−78° C.) solution of (S)-tert-butylallyl(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(8.70 g, 21 mmol) in diethylether was added tert-butyllithium (25 ml, 43mmol) dropwise. After stirred for 15 min, the fresh distilled3,3,3-trifluoro-2-methylpropanal (5.8 ml, 53 mmol) was added, and thereaction was stirred for 30 min, and then quenched with saturated NH4Cl.The resulted mixture was allowed to warm to RT and extracted with EtOAc(3×). The organic layers were combined, dried over Na2SO4, filtered andconcentrated. The residue was purified on silica gel column to affordthe title compound as a mixture of isomers (4.5 g, 46% yield) as lightyellow oil. MS m/z: 457 (M+1).

Step 2: tert-Butylallyl((S)-2,2-spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a cooled (−78° C.) solution of tert-butylallyl((S)-2,2-spirocyclobutyl-6-(3,3,3-trifluoro-1-hydroxy-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(1.24 g, 2.7 mmol) in toluene was added (diethylamino)sulfur trifluoride(0.54 ml, 4.1 mmol) via a syringe. The reaction was stirred for 50 min,then quenched with saturated NH₄Cl (10 ml) and warmed to RT. The layerswere separated. The aqueous layer was extracted with EtOAc (2×20 ml).The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The crude residue was purified on a silica gel column(10-15% EtOAc/hexane) to afford the title compound as a mixture ofisomers as colorless oil. MS m/z: 459 (M+1).

Step 3:(4S)—N-Allyl-2,2-spirocyclobutyl-6-(1,333-tetrafluoro-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amine

To a solution of tert-butylallyl((S)-2,2-spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(430 mg, 938 μmol) in MeOH was added hydrogen chloride 4.0 m in1,4-dioxane (2.0 ml, 8000 μmol). The reaction was stirred for 2 days(over the weekend) at RT, then concentrated and neutralized with 10%Na₂CO₃ and extracted with DCM (3×). The organic layers were combined,dried over Na₂SO₄ and filtered. The filtrate was concentrated and driedin vacuum to afford the title compound as a mixture of isomers as alight yellow oil. MS+ m/z: 359 (M+1).

Step 4:(4S)-2,2-Spirocyclobutyl-6-(1,3,3,3-tetrafluoro-2-methylpropyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amine

The crude product from step 3 above was dissolved in CH₂Cl₂ (10 ml) towhich 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (439 mg, 2814 μmol)was added. The mixture was purged with N₂ gas for 10 min andtetrakis(triphenylphosphine)palladium (0) (54 mg, 47 μmol) was added.The reaction was heated at 40° C. for 3 h, then cooled and diluted withDCM and washed with 10% Na₂CO₃ (2×). The aqueous layer was backextracted with EtOAc (2×). The organic layers were combined, dried overNa₂SO₄, filtered and concentrated. The residue was dried in vacuum toafford the title compound as mixture of isomers as a yellow oil. MS m/z:319 (M+1).

Example 28

(S)-2,2-Spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amineStep 1: (S)-tert-Butylallyl(2,2-spirocyclobutyl-6-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a cooled (−78° C.) solution of (S)-tert-butylallyl(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(19.85 g, 48 mmol) in THF (400 ml) was added butyllithium solution, ˜2.5m in toluene (21 ml, 53 mmol) dropwise via a syringe. After the additionwas completed, the mixture was stirred 15 min. At this point, methyltrifluoroacetate (5.4 ml, 53 mmol) was added, and the reaction mixturewas stirred for 60 min at the same temperature, then quenched byaddition of saturated NH4Cl (250 ml). The resulted mixture was allowedto warm to RT and the layers were separated. The aqueous layer was backextracted with EtOAc (3×). The organic layers were combined, dried overNa₂SO₄, filtered and concentrated. The residue was purified on a silicagel column (5-35% EtOAc/hexane) to afford the title compound as lightyellow oil. MS+ m/z: 445 (M+18).

Step 2: tert-Butylallyl((S)-2,2-spirocyclobutyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a solution of (S)-tert-butylallyl(2,2-spirocyclobutyl-6-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(20.0 g, 46.9 mmol) in EtOH (400 ml) was added sodium tetrahydroborate(1.77 g, 46.9 mmol). The mixture was stirred at RT for 15 h, and thenquenched with water. The resulted mixture was concentrated under reducedpressure. The aqueous residue was diluted with water and extracted withEtOAc (3×). The organic layers were combined, washed with brine, driedover Na₂SO₄, and filtered. The filtrate was concentrated and dried invacuum to afford the title compound as a mixture of isomers as brownoil. MS m/z: 429 (M+1).

Step 3.1-((S)-4-(Allylamino)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-6-yl)-2,2,2-trifluoroethanol

The title compound was prepared by a method analogous to that describedin step 3 of Example 27 above. MS m/z: 329 (M+1).

Step 4:1-((S)-4-amino-2,2-spirocyclobutyl-2H-pyrano(2,3-b)pyridine-6-yl)-2,2,2-trifluoroethanol

The title compound was prepared by a method analogous to that describedin step 4 of Example 27 above. MS m/z: 289 (M+1)

Step 5: tert-butyl(S)-2,2-spirocyclobutyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a solution of1-((S)-4-amino-2,2-spirocyclobutyl-2H-pyrano(2,3-b)pyridine-6-yl)-2,2,2-trifluoroethanol(10.3 g, 35.7 mmol) in DCM (450 ml) was added diisopropylethylamine(6.22 ml, 35.7 mmol) followed by di-tert-butyl dicarbonate (7.80 g, 35.7mmol). The mixture was stirred at RT for 15 h, the resulted suspensionwas filtered, and the solid was rinsed with DCM to afford the titlecompound as a white solid. MS m/z: 389 (M+1). The filtrate was washedwith 2 N HCl (2×). The organic layer was concentrated and aprecipitation was occurred. The resulted suspension was filtered. Thesolid was dried in vacuum to afford an additional amount of the titlecompound as a white solid. The filtrate was concentrated and purified ona silica gel column (30-35% EtOAc/hexane) to provide another crop of thetitle compound as a light yellow solid.

Step 6: tert-Butyl(S)-6-(1-chloro-2,2,2-trifluoroethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate

To a solution of tert-butyl(S)-2,2-spirocyclobutyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(5.00 g, 12.9 mmol) in toluene (120 ml) was added pyridine (1.04 ml,12.9 mmol) at RT. Sulfuryl dichloride (1.31 ml, 18.0 mmol) was thenadded to the reaction slowly via a syringe. After the addition wascompleted, the reaction was stirred at RT for 15 h, then heated at 45°C. for another 3 h. The resulted brown solution was cooled to RT anddiluted with water and EtOAc. The aqueous layer was back extracted withEtOAc (2×). The organic layers were combined, washed with brine, driedover Na2SO4, and filtered. The filtrate was concentrated and purified ona silica gel column (5-25% EtOAc/hexane) to afford the title compound asa mixture of isomers. MS m/z: 407 (M+1)

Step 7: (S)-tert-Butyl2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-ylcarbamate

A mixture of tert-butyl(S)-6-(1-chloro-2,2,2-trifluoroethyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-yl)carbamate(1.3 g, 4.9 mmol) and Palladium on carbon (0.7 g, 10% on carbon) inethanol (100 ml) was stirred under H₂ atmosphere (H₂ balloon) for 18 h.The reaction mixture was then filtered through celite. The filtrate wasconcentrated and dried in vacuum to afford the title compound as lightyellow solid. MS m/z: 373 (M+1).

Step 8:(S)-2,2-Spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-amine

To a solution of (S)-tert-butyl2,2-spirocyclobutyl-6-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-pyrano(2,3-b)pyridine-4-ylcarbamate(1.0 g, 3.0 mmol) in methanol was added hydrogen chloride 4.0 m in1,4-dioxane (5.0 ml, 20 mmol). After stirred for 3 h at RT, the reactionwas concentrated and dried in vacuum to afford the title compound as anoff-white solid. MS m/z: 273 (M+1).

Example 29

(S)-6-tert-Butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1:(S)-4-Azido-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-ol

A 25-mL RBF was charged with(S)-4-azido-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(0.100 g, 0.34 mmol), and the solid was dissolved in THF (3.0 mL). Thesolution was cooled to −780° C., and a solution of butyllithium (2.50 M,0.20 ml, 0.51 mmol) in hexane was added, followed immediately bytriisopropyl borate (0.079 ml, 0.34 mmol. After 45 minutes, the reactionsolution was warmed to 0° C. After 30 minutes, a mixture of aqueous 30%hydrogen peroxide (0.35 ml, 3.4 mmol), and sodium hydroxide (2.50 M,0.81 ml, 2.0 mmol) was added, and the mixture was warmed to ambienttemperature. After 30 minutes the mixture was concentrated, the cruderesidue was taken up in half-saturated NH₄Cl (10 mL) and extracted withDCM (3×20 mL). The organic layers were combined, dried over sodiumsulfate and concentrated. The crude material was purified through silicagel (25 mL) using 50% EtOAc-hexane to afford the title compound. MS m/z233 (M+1).

Step 2:(S)-4-Azido-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine

In a microwave vessel, the(S)-4-azido-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-ol(0.024 g, 0.10 mmol) was suspended in DCM (2 mL), andtrifluoromethanesulfonic acid (0.011 ml, 0.12 mmol) was added to themixture, The reaction mixture was cooled to −78° C. 2-Methylprop-1-ene(0.97 ml, 10 mmol) was separately liquefied at −78° C. and added to thereaction mixture via a pipet. The reaction vessel was sealed and allowedto warm to RT while stirring overnight. The reaction was diluted withDCM (60 mL), and the organic phase was extracted with dilute sodiumcarbonate (2×6 mL), then with dilute brine (6 mL). The organic phase wasdried over sodium sulfate, filtered and concentrated, and the cruderesidue was purified through silica gel (20 mL) using 38% EtOAc-hexaneto afford the title compound (15 mg, 0.052 mmol, 50%) as a white solid.MS m/z 289 (M+1).

Step 3:(S)-6-tert-Butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

In a 25-mL RBF, the(S)-4-azido-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine(0.036 g, 0.12 mmol) and Pd/C (10%, 0.0036 g) were taken up in EtOAc(2.5 mL), and the mixture was stirred at ambient temperature under anatmosphere of hydrogen. After 16 h, the mixture was filtered throughCelite, and the filtrate was concentrated. Purification of theconcentrate through silica gel (20 mL), which had been deactivated withtriethylamine (2 mL) using 0.5% MeOH-DCM, afforded the title compound.MS m/z 263 (M+1).

Example 30

6-(2′,2′-Dimethylpropyl)-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1: (±)6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-one

A mixture of6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-one(4.9 g, 18 mmol) and SLECTFLUOR (7.1 g, 20 mmol) in 40 ml of anhydrousMeOH was heated at 110-130° C. in a pressure bottle for 16 h. Themixture was cooled down and the solids were filtered off. The filtratewas concentrated to give an oil which was purified by silica gelchromatography using EtOAc-Hexanes (0-12%) to give the tile compound asa clear oil which solidified upon drying.

Step 2: (i)6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl-(S)-tert-butylsulfinylimine

A solution of (i)6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-one(3.0 g, 10 mmol) and (S)-2-methylpropane-2-sulfinamide (2.5 g, 21 mmol)in 5 ml of THF was treated with tetraethoxytitanium (8.7 ml, 42 mmol) atrt for 18 h. The reaction mixture was diluted with 100 ml of EtOAc andthe resulting solution was added dropwise to 150 ml of sat. aq. NaHCO₃.White precipitates formed, and the mixture was stirred at rt vigorouslyfor 1 h. The EtOAc layer was carefully decanted; the rest of mixture wasfiltered through a celite pad with Na₂SO₄. The celite pad was washedwith 150 ml of EtOAc. The filtrates were combined and the EtOAc layerwas separated. All organic layers were combined, dried (Na₂SO₄) andconcentrated to give an oil that was purified by Isco (0-30% EtOAc inhexanes) to give the title compound as a yellow foam.

Step 3:(4R)-6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

A solution of (±)6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl-(S)-tert-butylsulfinyliminefrom Step 2 (2.55 g, 6.6 mmol) in 20 ml of THF:H₂O (98:2) at −50° C. wastreated with sodium borohydride (0.74 g, 20 mmol) and the resultingmixture was stirred and warmed up to rt over 2 h, and then stirredovernight. The solvents were then removed, The crude residue wastriturated with DCM, washed with sat. aq. NaHCO₃ (2×75 ml), dried overNa₂SO₄ and concentrated to give the title compound as an oil.

Step 4: (4R)-tert Butyl6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-carbamate

A solution of(4R)-6-Bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine(1.23 g, 4.3 mmol) in 15 ml of dry DCM was treated with Boc anhydride(4.3 ml, 4.3 mmol) at rt overnight. The reaction solvent was removed andthe resulting crude residue was purified by ISCO (0-20% EtOAc onhexanes) to give the titled compound.

Step 5:(4R)-6-(2′2′-dimethylpropyl)-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

To a 50 mL RBF was added (4R)-tert butyl6-bromo-2,2-spirocyclobutyl-3-fluoro-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-carbamate(580 mg, 1498 μmol), dioxane (10 mL). The solution was degassed with N₂for 10 minutes, and Pd catalyst (53 mg, 75 μmol) was added to thesolution. A solution of neopentylzinc(II) iodide, in THF (8.0 ml, 4000μmol) was then added and the reaction mixture was stirred at RT under N₂for 16 hours. The reaction mixture was quenched with water (20 mL) andacidified to pH 2 with 1N HCl. The mixture was extracted with EtOAc(2×40 mL). The combined organic layers were washed with brine andconcentrated in vacuo to give a dark brown oil, which was then treatedwith MeOH (30 mL) and HCl (4M in dioxane, 10 mL) and stirred overnight.The material was concentrated in vacuo and taken up in DCM (5% MeOH wasadded to improve solubility), and extracted with 1N HCl (2×20 mL). Thecombined acidic aqueous layers were washed with DCM (20 mL), neutralizedwith sat'd NaHCO₃ and extracted with DCM (3×20 mL). The combined organiclayers were concentrated in vacuo to give the title compound.

Example 31

(4S)-6-(2′,2′-Dimethyl-3′,3′,3′-trifluoro-propyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amineStep 1: 1,1,1-Trifluoro-2-(4-methoxyphenyl)propan-2-ol

A solution of 1-bromo-4-methoxybenzene (19 ml, 150 mmol) in 300 ml ofdry THF at −78° C. was treated with n-butyllithium (96 ml, 154 mmol)(1.6 M or 15% in hexanes, Strem). The resulting mixture was stirred foran additional 30 min. At −78° C., 1,1,1-trifluoropropan-2-one (16 ml,180 mmol) was added and the mixture was stirred −78° C. and slowlywarmed up overnight. The reaction mixture was treated with 100 ml of 5NHCl and concentrated. The layers were separated. The bottom layer(organic) was diluted with 50 ml of DCM, washed with 1×100 ml of H₂O,and dried (MgSO₄) and concentrated to give an oil which was purified bysilica gel chromatography eluting with 0-5% EtOAc in hexanes to providethe title compound.

Step 2: 1-(2-chloro-1,1,1-trifluoropropan-2-yl)-4-methoxybenzene

A solution of 1,1,1-trifluoro-2-(4-methoxyphenyl)propan-2-ol (22.5 g,102 mmol) in 150 ml of anhydrous toluene was treated sequentially withpyridine (8.26 ml, 102 mmol) and dropwise sulfuryl dichloride (11.2 ml,153 mmol) at 0° C. The resulting mixture was then heated at 55° C. for18 h. The reaction was diluted with 100 ml of EtOAc, washed with 100 mlof H₂O and 100 ml of 1N HCl, dried over Na₂SO₄, and concentrated to givean oil which was filtered through a silica gel pad eluting with 0-5%EtOAc in hexanes to afford the title compound.

Step 3: 1-Methoxy-4-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene

A solution of 1-(2-chloro-1,1,1-trifluoropropan-2-yl)-4-methoxybenzene(18.0 g, 75 mmol) in 400 ml of hexanes was treated withtrimethylaluminum (151 ml, 302 mmol) (2.0 M in heptane) at rt and theresulting mixture was heated at 95° C. overnight. The reaction mixturewas cooled in an ice-water bath, conc. HCl was added to the reactionmixture dropwise. Fumes were generated. After about 10 ml of conc. HClwas added, more rapid addition of acid was possible due to the nearcomplete quenching of the unreacted AlMe3. After addition of 100 ml ofconc. HCl, 250 ml of H₂O was added and the mixture was stirredvigorously for 1 h. The layers were separated. The org layer was dried(Na₂SO₄) and concentrated to give the title compound as an oil, whichsolidified upon drying on the vac line.

Step 4: 3,3,3-Trifluoro-2,2-dimethylpropanoic acid

To a biphasic mixture of1-methoxy-4-(1,1,1-trifluoro-2-methylpropan-2-yl)benzene (10.0 g, 45.8mmol) and sodium periodate (137 g, 642 mmol) in a mixture solvent ofCCl₄:CH₃CN:H₂O (2:2:3, 550 ml) was added slowly ruthenium(III) chloridehydrate (0.517 g, 2.29 mmol) (black powder) while the reaction flask waskept in an ice-water bath. The mixture turned yellow rapidly then redafter 5 minutes, ans was stirred for 0.5 h. The ice-water bath wasremoved and the reaction mixture was stirred vigorously, via amechanical stirrer, overnight. The solids were filtered off, washed with100 ml of DCM, 100 ml of H₂O. The filtrate (pH ˜1) was basified with 10N NaOH to pH>11, and the layers were separated, and the aq. layer wasextracted with 130 ml of DCM. The aq. layer was then acidified carefullywith conc. HCl to pH ˜1, extracted with 3×150 ml of DCM. The org layerswere combined, dried (Na₂SO₄), and concentrated to give the titlecompound as an oil, which became a semi-solid upon drying on the vacline.

Step 5: Naphthalen-2-ylmethyl 3,3,3-trifluoro-2,2-dimethylpropanoate

A mixture of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (2.96 g, 19.0mmol), 2-(bromomethyl)naphthalene (4.19 g, 19.0 mmol), and potassiumcarbonate (7.86 g, 56.9 mmol) in 50 ml of anhydrous DMF was stirred at30° C. overnight. Diluted with 150 ml of EtOAc, washed with 150 ml ofH₂O, 2×100 ml of 1N NaOH, 2×100 ml of 1N HCl, dried (Na₂SO₄) andconcentrated to give an oil that was purified by ISCO using EtOAc inhexanes (5%) as eluents to provide the title compound as an oil.

Step 6:(4S)-6-(2′,2′-dimethyl-3′,3′3′-trifluoro-propyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine

The title compound was obtained by a method analogous to the method ofthe last step described in Example 28 above.

Example 32

(4S)-6-Neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]-2,3-dihydropyrano[2,3-b-]pyridin-4-amineStep 1: 3-Cyanocyclobutanone

To a stirred mixture of 3-methylenecyclobutanecarbonitrile (5.0 g, 54mmol) and ruthenium trichloride hydrate (0.086 ml, 1.2 mmol) inDCM/MeCN/H₂O (215/215/315 ml) was added sodium meta periodate (12 ml,225 mmol) in several portions (30 min.). The reaction mixture was slowlywarmed to RT and stirred in 3 h. The precipitated solid was filteredoff. The filtrate was extracted with DCM (3×); dried over MgSO₄,concentrated and filtered through a short plug of silical gel,concentrated, to give the title compound as a light brown oil, whichsolidified upon standing at rt.

Step 2: 3-(2-(5-Bromo-2-methoxypyridin-3-yl)-2-oxoethylidene)cyclobutanecarbonitrile

A mixture of lithium(Z)-1-(5-bromo-2-methoxypyridin-3-yl)-2-(dimethoxyphosphoryl)ethenolate(2.0 g, 5.8 mmol) and 3-oxocyclobutanecarbonitrile (1.1 g, 12 mmol) inp-dioxane (6 ml) was heated at 120° C. by Microwave in 1 h. The mixturewas cooled, taken up in H₂O, extracted with EtOAc (3×), dried overMgSO₄, concentrated to provide the title compound. MS (m+1): 307.0.

Step 3:6-Bromo-[(2,2-spirocyclobutyl)-3′-cyano)]2,3-dihydropyrano[2,3-b-]pyridine-4-one

A mixture of 3-(2-(5-bromo-2-methoxypyridin-3-yl)-2-oxoethylidene)cyclobutanecarbonitrile (3.4 g, 11 mmol), sodium iodide (1.8 ml, 44mmol), and chlorotrimethyl silane (5.6 ml, 44 mmol) in MeCN (40 ml) wasstirred at rt for 24 h, concentrated, taken up in H₂O, extracted withDCM (3×), washed with saturated NH₄Cl, brine, dried over MgSO₄,concentrated and purified by ISCO (20% EtOAc/Hexanes) to give the titlecompound as a yellow solid.

Step 4:(4R)-6-Bromo-[(2,2-spirocyclobutyl)-3′-cyano)]2,3-dihydropyrano[2,3-b-]pyridine-4-ol

To a stirred solution of (S)-2-methyl-CBS-oxazaborolidine (1M intoluene; 1.0 ml, 1.0 mmol) in toluene (5 ml) was added a solution ofborane-methyl sulfide complex (0.5 ml, 5 mmol) in toluene (20 ml) and asolution of6-bromo-[(2,2-spirocyclobutyl)-3′-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-one(1.40 g, 5 mmol) in toluene (20 ml) in 30 min at 0° C. The reactionmixture was stirred for another 15 min. then slowly quenched with 10%aq. HCl, extracted with EtOAc (3×), washed with NaHCO₃, brine, driedover MgSO₄, concentrated to give the title compound as a light yellowsolid. MS (m+1): 296.1

Step 5:(4R)-6-Bromo-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3′-cyano)]2,3-dihydropyrano[2,3-b-]pyridine

To a stirred mixture of(4R)-6-bromo-[(2,2-spirocyclobutyl)-3′-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-ol(5.7 g, 19 mmol) and 1H-imidazole (22 ml, 193 mmol) in DMF (70 ml) wasadded tert-butylchlorodimethylsilane (15 g, 97 mmol). The reactionmixture was stirred at rt in 24 h, added water, extracted with ether(3×), dried over MgSO₄, concentrated and purified by ISCO (15%EtOAc/Hexanes) to give the title compound. MS (m+1): 410.4.

Step 6:(4R)-6-(2′2-dimethylpropyl)-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3′-cyano)]2,3-dihydropyrano[2,3-b-]pyridine

To a stirred solution of neopentylmagnesium chloride (1M, 15 ml, 15mmol) at 0° C. was added dropwise a solution of zinc(II) chloride (8 ml,8 mmol). The mixture was gradually warmed to rt in 30 min. PdCl₂(dppf)₂(0.2 g, 0.2 mmol) and a solution of(4R)-6-bromo-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3′-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine(1.56 g, 4 mmol) in THF (20 ml) were successively added to the mixture.The reaction mixture was stirred at 40° C. overnight, then cooled,quenched with saturated NH₄Cl, extracted with EtOAc, dried over MgSO₄,concentrated to provide the title compound. MS (m+1): 401.6.

Step 7:(4R)-6-Neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-oland(4R)-6-neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-ol

To a stirred solution of(4R)-6-neopentyl-4-tert-butyldimethylsilyloxo-[(2,2-spirocyclobutyl)-3′-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine(1.5 g, 4 mmol) in THF (10 ml) was added tetrabutylammonium fluoride,1.0M in THF (7 ml, 7 mmol). The reaction mixture was stirred in 2 h,quenched with H₂O, extracted with EtOAc, dried over MgSO₄, concentratedand purified by ISCO (40% EtOAc/Hexanes with 120 g column) to separatethe cis- and trans-isomers of the title compound. MS (m+1): 287.4.

Step 8:(4S)-4-Azido-6-neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]2,3-dihydropyrano[2,3-b-]pyridine

To a stirred solution of(4R)-6-neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-ol(1.05 g, 3.67 mmol) in toluene (30 ml) was added DPPA (1.03 ml, 4.77mmol) dropwise. After stirring for 15 min., DBU (0.713 ml, 4.77 mmol)was slowly added, and the reaction mixture was stirred at RT for 16 h.H₂O was added and the mixture was extracted with EtOAc (3×), washed withbrine, dried over MgSO₄, concentrated to give the title compound as abrown oil. MS (m+1): 312.4.

Step 9:(4S)-6-Neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]-2,3-dihydropyrano[2,3-b-]pyridin-4-amine

A mixture of(4S)-4-azido-6-neopenyl-[(2,2-spirocyclobutyl)-3′-cis-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine(3 g, 10 mmol) and triphenylphosphine (3 g, 10 mmol) in THF (20 ml) wasstirred at RT in 2 h, 3 ml of H₂O was added and heated at 80° C. in 4 h.40 ml of 10% aq. HCl was added and the mixture was heated for 10 min. at80° C., then cooled and extracted with toluene, (discarded). The acidicaqueous layer was neutralized with solid Na₂CO₃, extracted with DCM(3×), dried over MgSO₄, purified by ISCO (3% MeOH/DCM) to give the titlecompound as a yellow foam. MS (m+1): 286.4.

Example 33

(4S)-6-Neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridin-4-amineStep 1:(4S)-4-Azido-6-neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine

To a stirred solution of(4R)-6-neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine-4-ol(2.6 g, 9.1 mmol) in toluene (50 ml) was added diphenylphosphoryl azide(2.9 ml, 14 mmol) dropwise. After the addition, the mixture was stirredfor 15 min., cooled in an ice bath and DBU (2.0 ml, 14 mmol) was addedthereto dropwise. The reaction mixture was stirred at RT overnight,quenched with H₂O, extracted with ether (3×), dried over MgSO₄,concentrated to give the title compound as a brown oil. MS (m+1): 312.4.

Step 2:(4S)-6-neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridin-4-amine

To a stirred solution of(4S)-4-azido-6-neopenyl-[(2,2-spirocyclobutyl)-3′-trans-cyano)]-2,3-dihydropyrano[2,3-b-]pyridine(3 g, 10 mmol) in THF (50 ml) was added triphenylphosphine (3 g, 10mmol). The mixture was stirred at RT in 1 h, 10 ml of H₂O was added andstirred at 85° C. for 24 h, added 10% aq. HCl, stirred, cooled,extracted with toluene (discarded). The aqueous layer was neutralizedwith solid Na₂CO₃, extracted with DCM (3×), dried over MgSO₄,concentrated, purified by ISCO (3% MeOH/DCM) to give the title compoundas a light yellow solid. MS (m+1): 286.4.

Example 34

(S)-6-Bromo-N⁸-ethyl-2,2,-spirocyclobutyl-3,4-dihydro-2H-chromene-4,8-diamineStep 1: 1-(3-amino-5-bromo-2-hydroxyphenyl)ethanone

A mixture of 1-(5-bromo-2-hydroxy-3-nitrophenyl)ethanone (25 g, 96mmol), iron (27 g, 481 mmol), and NH₄Cl (5.1 g, 96 mmol) in EtOH/H₂O(5:1, 300 ml) was heated at reflux in 2 h, the mixture was cooledfiltered the solid, the filtrate was concentrated, taken up in H₂O,extracted with DCM (3×), dried over MgSO₄, concentrated and purified byISCO (10% EtOAc/Hexanes) to give the title compound as a yellow solid.MS (m+2): 232.1.

Step 2: 8-Amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one

A mixture of 1-(3-amino-5-bromo-2-hydroxyphenyl)ethanone (4.5 g, 20mmol), cyclobutanone (3 ml, 39 mmol), and pyrrolidine (5 ml, 59 mmol) inp-dioxane (80 ml) was heated at 65° C. for 24 h. The mixture was cooled,taken up in dilute acid, stirred, extracted with EtOAc (3×), dried overMgSO₄, concentrated and purified by ISCO (0-20% in 30 min.) to give thetitle compound as an orange solid. MS (m+2): 284.1.

Step 3: (4R)-8-Amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-ol

To a stirred solution of (s)-2-methyl-CBS-oxazaborolidine, IM in toluene(1 ml, 1 mmol) in toluene (2 ml) was added a solution of borane-methylsulfide complex (5 ml, 11 mmol) in toluene (20 ml) followed by additionof a solution of8-amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one (3 g, 11mmol) in toluene (40 ml) dropwise. After the reaction was complete asmonitored by TLC, it was quenched with 10% aq. HCl (40 ml), stirred for15 min., extracted with EtOAc (3×), washed with brine, dried over MgSO₄,filtered and concentrated to give the title compound as a purple foam.MS (M+1): 285.2.

Step 4:(4R)-8-Amino-6-bromo-4-tertbutyldimethylsilyloxo-2,2-spirocyclobutyl-2,3-dihydrochromene

A mixture of 8-amino-6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-ol(3.2 g, 11 mmol) and imidazole (1 ml, 12 mmol) in DCM (30 ml) was addedtert-butylchlorodimethylsilane (2 g, 12 mmol). The mixture was stirredfor 3 h, then H₂O was added and the layers were separated, dried overMgSO₄, concentrated and the crude was purified by ISCO (5%EtOAc/Hexanes) to give the title compound as a colorless oil. MS (M+1):399.4.

Step 5:(4R)-8-ethylamino-6-bromo-4-tertbuldimethylsilyloxo-2,2-spirocyclobutyl-2,3-dihydrochromene

A mixture of(4R)-8-amino-6-bromo-4-tertbutyldimethylsilyloxo-2,2-spirocyclobutyl-2,3-dihydrochromene(2 g, 5 mmol), acetaldehyde (0.3 ml, 5 mmol), and trimethyl orthoformate(4 ml, 40 mmol) in DCE (20 ml) was stirred at RT in 30 min. Sodiumtriacetoxyborohydride (5 g, 25 mmol) was added and stirred in 3 h,quenched with diluted aq. HCl, extracted with DCM (3×), dried overMgSO₄, concentrated and purified by ISCO (5% EtOAc/Hexanes) to give thetitle compound as a light yellow oil. MS (M+1): 428.4.

Step 6:(4R)-6-Bromo-8-(ethylamino)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ol

To a mixture of(4R)-8-ethylamino-6-bromo-4-tertbutyldimethylsilyloxo-2,2-spirocyclobutyl-2,3-dihydrochromene(0.900 g, 2.2 mmol) in THF (15 ml) was added tetrabutylammonium fluoride(2.6 ml, 2.6 mmol). The reaction mixture was stirred at RT for about 2h. H₂O was added and the mixture was extracted with EtOAc (3×), driedover MgSO₄, concentrated to give the title compound as a brown oil. MS(M+1): 304.4.

Step 7:(S)-6-Bromo-N⁸-ethyl-2,2,-spirocyclobutyl-3,4-dihydro-2H-chromene-4,8-diamine

The title compound was obtained as a white foam, by a method analogousto that described in Steps 7-8 of Example 9 above. MS (M+1): 312.2.

Example 35

(S)-2,2-Spirocyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4-amineStep 1: 5-Methoxymethoxy)-2-(trifluoromethyl)pyridine

To a stirred suspension of NaH (3.1 ml, 74 mmol) in DMF (100 ml) wasadded 6-(trifluoromethyl)pyridin-3-ol (10 g, 61 mmol) in severalportions. The mixture was stirred for 30 min., then chlorodimethyl ether(5.0 ml, 64 mmol) was added dropwise and stirring was continued for 3 h.The reaction was cooled to 0° C. and quenched slowly by addition of H₂O.The solution was extracted with ether (3×), the organic layers weredried over MgSO₄, filtered and concentrated to give the title compoundas a yellow oil. MS (M+1): 208.2.

Step 2: 1-(5-(Methoxymethoxy)-2-(trifluoromethyl)pyridine-4-yl)ethanol

To a stirred solution of piperidine, 2,2,6,6-tetramethyl-(9.2 ml, 54mmol) in THF (400 ml) at −78° C. was added butyllithium (−2.5 m intoluene; 18 ml, 45 mmol) dropwise. The reaction was then stirred at 0°C. for 5 min at −78° C., and a solution of5-(methoxymethoxy)-2-(trifluoromethyl)pyridine (7.5 g, 36 mmol) in THF(100 ml) was added dropwise. The mixture was stirred for an additional10 min, then acetaldehyde (20 ml, 362 mmol) was added and stirringcontinued for 15 min. the reaction was slowly quenched with H₂O, warmedto RT, extracted with EtOAc (3×), combine organic layers were dried overMgSO₄, filtered, concentrated and the crude product was purified by ISCO(20% EtOAc/Hexanes) to give the title compound as a light yellow solid.MS (m+1): 252.2.

Step 3: 1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone

To a stirred mixture of1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanol (3.2 g, 13mmol) and NaHCO₃ (3.2 g, 38 mmol) in DCM (100 ml) was added Dess MartinPeriodinane (5.9 g, 14 mmol). The reaction mixture was stirred at rt in16 h, the solid was filtered, the filtrate was concentrated, then takenup and stirred in ether/EtOAc. The precipitated white solids werefiltered and discarded. The filtrate was concentrated to give the titlecompound as a light yellow oil. MS (m+1): 250.2.

Step 4: 1-(5-hydroxy-2-(trifluoromethyl)pyridin-4-yl)ethanone

A mixture of1-(5-(methoxymethoxy)-2-(trifluoromethyl)pyridin-4-yl)ethanone (3.2 g,13 mmol) and 5N (40 ml) in i-PrOH/THF (1:1, 40 ml) was stirred at 45° C.overnight. The mixture was cooled, concentrated, taken up in H₂O,neutralized with saturated NaHCO₃, and extracted with DCM (3×). Theorganic layers were combined, dried over Na₂SO₄, and concentrated togive the title compound as a tan solid. MS (m+1): 206.2

Step 5:(S)-2,2-Spirocyclobutyl-6-trifluoromethyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4-amine

The title compound was obtained by a method analogous to that describedin Steps 6-8 of Example 9 above. MS (m+1): 259.2.

Example 36

(4S)-[(2,2-Spirocyclobutyl-3′(trans)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H-chromen-4-amineand(4S)-[(2,2-Spirocyclobutyl-3′(cis)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H-chromen-4-amineStep 1: 2,2-Dichloro-3-oxocyclobutyl pivalate

To a stirred mixture of vinyl pivalate (30 g, 234 mmol) and zinc (31 g,468 mmol) in ether (300 ml) was added a solution of2,2,2-trichloroacetyl chloride (55 g, 304 mmol) in ether (300 ml)dropwise (2-3 h) in a water bath. (Note: fast addition causes thereaction temp to elevate) while maintaining the reaction temperaturebetween 15-30° C. After the reaction was done (stained with KMnO₄solution), it was filtered through Celite. The filtrate was washed withcold water, brine, dried over MgSO₄ and concentrated to give the titlecompound as an orange solid.

Step 2: 3-Oxocyclobutyl pivalate

To a stirred suspension of zinc dust (103 g, 1568 mmol) in HOAc (200 ml)was added a solution of 2,2-dichloro-3-oxocyclobutyl pivalate (75 g, 314mmol) in HOAc (400 ml) dropwise in an ice bath. The reaction mixture wasstirred for 1 h, filtered the solid through celite and washed with DCM.The DCM layer was washed with H₂O, NaHCO₃, brine, dried over MgSO₄,filtered and concentrated. The crude material was purified by ISCO (10%EtOAc/Hexanes) to give the title compound as a light yellow oil.

Step 3: 3-Hydroxylcyclobutyl pivalate

To a stirred solution of 3-oxocyclobutyl pivalate (15.1 g, 88.7 mmol) inethanol (100 ml) at 0° C. was added sodium borohydride (4.69 ml, 133mmol) in several portions. The reaction was stirred for 30 min, slowlyquenched with 10% aqueous HCl and concentrated to remove ethanol. Thesolution was taken up with more 10% HCl, extracted with DCM (3×), washedwith brine, dried over MgSO₄ and concentrated to give the title compoundas a light yellow oil.

Step 4: 3-(tert-Butyldimethylsilyloxy)cyclobutyl pivalate

To a stirred mixture of 3-hydroxycyclobutyl pivalate (16.60 g, 96.4mmol) and diea (25.2 ml, 145 mmol) in DCM (100 ml) at 0° C. was addedtert-butyldimethylsilyl triflate (31.0 ml, 135 mmol) dropwise. Thereaction was stirred for 2 h, then quenched with H₂O. The layers wereseparated, and the organic layer was washed with saturated NaHCO₃,brine, dried over MgSO₄ and concentrated to give the title compound as alight brown oil.

Step 5: 3-(tert-butyldimethylsilyloxy)cyclobutanol

To a stirred solution of 3-(tert-butyldimethylsilyloxy)cyclobutylpivalate (4.32 g, 15 mmol) in THF (20 ml) at 0° C. was addeddiisobutylaluminum hydride, 1.0 m solution in hexanes (48 ml, 48 mmol)dropwise. The reaction was stirred in 1 h, then slowly quenched withRochelle's salt. The quenched mixture was stirred and layers wereseparated. The organic layer was dried over MgSO₄ and concentrated togive the title compound as a colorless oil.

Step 6: 3-(tert-butyldimethylsilyloxy)cyclobutanone

A mixture of 3-(tert-butyldimethylsilyloxy)cyclobutanol (2.59 g, 13mmol), sodium bicarbonate (3 ml, 38 mmol), and Reactant 1 [?] (7 g, 15mmol) in DCM (40 ml) was stirred at RT in 4 h, the solid was filtered;the filtrated was purified by ISCO (5% EtOAc/Hexanes) to give the titlecompound as a colorless oil.

Step 7: (4S)-[(2,2-Spirocyclobutyl-3′(trans)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H-chromen-4-amine and(4S)-[(2,2-Spirocyclobutyl-3′(cis)-hydroxyl)]-6-neopentyl-3,4-dihydro-2H-chromen-4-amine

The title compounds were obtained, by a method analogous to thatdescribed in Steps 6-8 of Example 9 above, after separation of the cis-and trans-isomers by reverse phase HPLC. MS (m+1): 261.2.

Example 37

1-(3-(Methoxymethoxy)pyridin-4-yl)ethanone Step 1:3-(methoxymethoxy)pyridine

Pyridin-3-ol (25 g, 260 mmol) was added to a stirring mixture of NaH (11g of a 60 wt % dispersion with mineral oil, 260 mmol) and DMF (350 mL)at 0° C. After 30 min, the reaction mixture was allowed to warm to RT,stirred for 90 min, and then chloromethoxymethane (20 mL, 260 mmol) wasadded. After 18 h, the reaction mixture was partitioned between ethylacetate and saturated aqueous NaHCO₃, the layers were separated, theorganic layer was washed with saturated aqueous NaHCO₃, brine, dried(Na₂SO₄), filtered, and the filtrate was concentrated. The residue wasdissolved with CH₂Cl₂, the solution was filtered through a plug ofsilica gel (sequential elution; 9:1→1:1 hexane-ethyl acetate), and thesecond filtrate was concentrated to give 10 g (27%) of3-(methoxymethoxy)pyridine as a clear yellow oil.

Step 2: 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol

A solution of 3-(methoxymethoxy)pyridine (9.8 g, 70 mmol) and THF (40mL) was added to a stirring mixture of tert-butyllithium (91 mL of a 1.7M solution with pentane, 160 mmol) and THF (100 mL) at −780° C. After 1h, acetaldehyde (9.9 mL, 180 mmol) was added, and the reaction mixturewas stirred for 3 h and then warmed to RT. After 21 h, the reactionmixture was partitioned between ethyl acetate and saturated aqueousNaHCO₃, the layers were separated, the organic material was washed withsaturated aqueous NaHCO₃, brine, dried (Na₂SO₄), filtered, and thefiltrate was concentrated. The residue was purified by flashchromatography on silica gel (1:1 hexane-ethyl acetate) to afford 4.6 g(36%) of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol as a colorless solid.

Step 3: 1-(3-(methoxymethoxy)pyridin-4-yl)ethanone

Dess-Martin periodinane (18 g, 43 mmol) was added to a stirring mixtureof 1-(3-(methoxymethoxy)pyridin-4-yl)ethanol (4.6 g, 25 mmol), NaHCO₃(6.3 g, 75 mmol), and CHCl₃ (75 mL) at RT. After 24 h, 1.0 M aqueousNa₂S₂O₃ was added, the reaction mixture was stirred for 90 min,partitioned between ethyl acetate and 1.0 M aqueous Na₂S₂O₃, the layerswere separated, the organic layer was washed with 1.0 M aqueous Na₂S₂O₃,water, brine, dried (Na₂SO₄), filtered, and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (gradient elution; 2:1→1:1 hexane-ethyl acetate) to give 3.9 g (86%)of 1-(3-(methoxymethoxy)pyridin-4-yl)ethanone as a clear yellow-orangeoil.

Example 38

2-Isopropoxyacetic acid Step 1: tert-Butyl 2-isopropoxyacetate

In a 250-mL flask, 35% aqueous sodium hydroxide (29.3 g, 256 mmol),propan-2-ol (0.785 ml, 10.3 mmol) tetrabutylammonium chloride (0.214 g,0.769 mmol), and tert-butyl 2-bromoacetate (1.00 g, 5.13 mmol) weretaken up in benzene (25 mL). The mixture was stirred at ambienttemperature overnight. The reaction was concentrated to remove most ofthe benzene. The aqueous residue was diluted further with water (100 mL)and the aqueous phase was extracted with 75% ether-hexane (3×33 mL). Theorganics were combined, washed with water (10 mL) then with saturatedbrine (10 mL). The organics were dried over magnesium sulfate, filtered,and concentrated to afford the title compound (119 mg, 0.683 mmol, 13%).

Step 2: 2-Isopropoxyacetic acid

In a 25-mL RBF, the tert-butyl 2-isopropoxyacetate (0.120 g, 0.69 mmol)was dissolved in DCM (1.5 mL). The solution was cooled to 0° C. TFA(0.53 ml, 6.9 mmol) was added, and the solution was stirred at 0° C. for30 min. Then the ice bath was removed and the mixture was stirred atambient temperature overnight. The mixture was then concentrated toafford the title compound.

Example 39

Lithium 2-methoxybutanoate Step 1: Methyl 2-methoxybutanoate

A 250-mL RBF was charged with DMSO (15 mL). n-Butyllithium (2.50 M, 8.45ml, 21.1 mmol) was added to the mixture as a solution in hexane. Asolution of 2-hydroxybutanoic acid (1.00 g, 9.61 mmol) was dissolved inDMSO (15 mL). The solution was transferred via cannula into the dimsylanion reaction mixture. The resulting mixture was stirred at ambienttemperature for 2.5 h. Iodomethane (1.44 ml, 23.1 mmol) was added andthe reaction mixture was stirred overnight. The mixture was diluted withwater (125 mL) and the aqueous layer was extracted with ether (50 mL).The organic layer was washed with water (2×5 mL), then with saturatedbrine (5 mL), then was dried over magnesium sulfate, filtered, andconcentrated to afford the title compound.

Step 2: Lithium 2-methoxybutanoate

In a 15-mL RBF was dissolved methyl 2-methoxybutanoate (0.027 g, 0.20mmol) in methanol (0.75 mL). A solution of lithium hydroxide monohydrate(0.0086 g, 0.20 mmol) in water (0.75 mL) was added, and the mixture wasstirred overnight. The mixture was concentrated to afford the titlecompound.

Example 40

Lithium 2-ethoxycyclopropanecarboxylate (as a mixture of enantiomers andcis- and trans-isomers)

In a 250 mL RBF, ethyl vinyl ether (4.2 ml, 44 mmol) was dissolved inDCM (20 mL). Rhodium (II) acetate dimer (0.019 g, 0.044 mmol) was addedas a green powder, and ethyl diazoacetate (0.91 ml, 8.8 mmol) was addedas a solution in DCM (4 mL) to the reaction mixture. The mixture wasstirred overnight and concentrated. The crude mixture was dissolved inMeOH (0.75 mL), and lithium hydroxide hydrate (0.014 g, 0.34 mmol) wasadded as a solution in water (0.75 mL). The reaction mixture was stirredovernight, then concentrated and the title compound was used withoutpurification.

Example 41N-((1S,2R)-3-(((4′S)-6′-(acetylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

To a microwave vial was addedN-((2S,3R)-4-((S)-6-bromo-3,4-dihydrospiro[cyclobutane-1,2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide(0.050 g, 0.10 mmol), followed by cuprous iodide (0.00097 g, 0.0051mmol), acetamide (0.0066 g, 0.11 mmol), POTASSIUM CARBONATE (0.028 g,0.21 mmol), trans-1,3-cyclohexanebis(methylamine) (0.0016 ml, 0.010mmol) and toluene (1 mL). The mixture was heated to 150° C. in themicrowave for 1 hour. The reaction was cooled to RT and diluted withEtOAc. The solution was concentrated on silica gel and purified using anISCO chromatography system eluting with a solvent gradient of 0-100% DCMto DCM/MeOH/NH4OH (90:10:1). Collected product fractions andconcentrated in vaccuo to afford a yellow oil. A minimal amount of MeOHwas added to the oil followed by water. The solution was frozen andlypholized overnight to yield the title compound as a white solid. FoundMS m/z: 471.1 (M+1).

Example 42N-((1S,2R)-1-fluoro-3-hydroxy-4-((S)-6-neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)acetamideStep 1: Methyl 2-fluoro-2-phenylacetate

To a 1.0 L RBF containing NaHMDS (5.16 g, 28.1 mmol) was added THF (100mL) and the mixture was allowed to stir at −780° C. for 10 min. At thistime, methyl 2-phenylacetate (3.25 g, 21.6 mmol) was taken up in THF (15ml) and added dropwise to the reaction, which was then placed in a 0° C.bath for 40 min before being rechilled to −78° C. for 10 min. At thistime, NFSI (8.87 g, 28.1 mmol) was added in THF (930 ml) and the flaskwas placed in a 0° C. bath. The reaction was allowed to stir for 30 minwhen a white solid appeared. The reaction was allowed to stir for anadditional 20 min and then poured into ammonium chloride (200 ml) andextracted with EtOAc (3×100 ml). The combined organics were washed withsodium carbonate (10%, 3×100 ml) and brine. The solution was dried withsodium sulfate, filtered and concentrated to give 6.7 g of a yellow oil.A white solid formed upon storage on the bench. The crude mixture waspurified on a 330 g ISCO column (gradient of 20 to 50% EtOAc in hexanes)to give pure methyl 2-fluoro-2-phenylacetate as a pale yellow oil. (3.10g, 85.2% yield).

Step 2: 2-Fluoro-2-phenylacetaldehyde

To a 500 mL RBF containing 2-fluoro-2-phenylethanol (440.00 mg, 3139μmol) was added DCM (30 mL) and the mixture was allowed to stir at 23°C. for 5 min. At this time, sodium bicarbonate (343 mg, 4081 μmol) andDess-MartinPeriodinane (1731 mg, 4081 μmol) were added in one portionand the reaction mixture was allowed to stir for 15 min before thereaction was quenched by the addition of sodium thiosulfate (2482 mg,15697 μmol) in water (50 ml) and sodium bicarbonate (sat, 50 ml) anddiethyl ether (100 ml). The quenched reaction was allowed to stir for 20min and the organic layer was washed with sodium bicarbonate (sat., 3×75ml) and brine. The organic layer was dried over magnesium sulphate,filtered and concentrated to give the title compound (385 mg) as a paleyellow oil.

Step 3:(R,E)-N-(2-fluoro-2-phenylethylidene)-2-methylpropane-2-sulfinamide

To a 500 mL RBF containing 2-fluoro-2-phenylacetaldehyde (320.00 mg,2316.5 μmol) was added DCM (10 mL) and the mixture was allowed to stirat 23° C. for 2 min. At this time, (R)-2-methylpropane-2-sulfinamide(364.99 mg, 3011.5 μmol) was added in one portion to the mixturefollowed by copper(II) chloride (856.51 mg, 6370.4 μmol) at 5:30 μm. Thereaction was allowed to stir overnight and then filtered through a plugof celite over silica gel. The solvent was removed and the crude residuewas purified on a silica gel column (15 to 35% EtOAc in hexanes) to givethe product (168 mg, 30%).

Step 4:(R)—N—((R)-1-fluoro-1-phenylbut-3-en-2-yl)-2-methylpropane-2-sulfinamide

To a 250 mL RBF containing(10R,E)-N-(2-fluoro-2-phenylethylidene)-2-methylpropane-2-sulfinamide(672.00 mg, 2785 μmol) was added THF (15 mL) and the mixture was allowedto stir at −78° C. for 10 min. At this time, BF3.OEt2 (706 μl, 5569μmol) was added via syringe and the reaction was allowed to stir for 5min before adding to it vinylmagnesium bromide (2785 μl, 2785 μmol)dropwise via syringe. The reaction was allowed to stir for 30 min andthen quenched with ammonium chloride (sat, 120 ml). The aqueous layerwas extracted with EtOAc (3×75 ml). The combined organics were washedwith brine, dried over sodium sulfate, filtered and concentrated to give800 mg of crude oil that was purified on a silica gel column. Thefollowing product fractions were isolated: Fraction 1: slightly higher,104 mg, one diasteromer only. Rf=0.30 in 35% EtOAc in hexanes, UVactive, stains brown to anisaldehyde. Fraction 2: the rest, a mixture ofdiastereomers, 425 mg. The lower Rf diasteromer is just below the higherRf diasteromer spot. Interestingly, the lower Rf spot is UV active andstains yellow to anisaldehyde and not brown.

Step 5: (R)-Tert-butyl 1-fluoro-1-phenylbut-3-en-2-ylcarbamate

To a 150 mL RBF containing(R)—N-((1S,2R)-1-fluoro-1-phenylbut-3-en-2-yl)-2-methylpropane-2-sulfinamide(107.00 mg, 397 μmol) was added methanol (5 mL) and the mixture wasallowed to stir at 0° C. for 10 min. At this time, HCl (4N) (993 μl,3972 μmol) was added and the reaction was allowed to stir for 30 min.Then TEA (1384 μl, 9930 μmol) was added to the mixture followed by DCM(2 ml) and BOC₂O (173 mg, 794 μmol) in one portion. The reaction wasallowed to stir overnight and then the bulk of the methanol was removedby evaporation. The residue was dissolved in EtOAc and washed with HCL(0.5 N, 2×40 ml). The combined aqueous layers were back extacted withEtOAc. The combined organics were washed with sodium bicarbonate (1×50ml, sat) and brine and then dried with sodium sulfate. The driedsolution was passed though a plug of silica gel to give tert-butyl(1S,2R)-1-fluoro-1-phenylbut-3-en-2-ylcarbamate (111.0 mg). Rf=0.45 in20% EtOAc in hexanes, UV active and stain yellow to anisaldehyde. LC/MSgive an ionization for eliminated product (mass=190).

Step 6: (R)-tert-butyl1-fluoro-3,4-dihydroxy-1-phenylbutan-2-ylcarbamate

To a 250 mL RBF containing tert-butyl(1S,2R)-1-fluoro-1-phenylbut-3-en-2-ylcarbamate (105.00 mg, 396μmol)(mixture of diasteromers at benzylic fluoride stereocenter) wasadded tert-butanol (3 mL) and water (1 ml). The mixture was allowed tostir at 23° C. for 2 min, then NMO (139 mg, 1187 μmol) and osmiumtetraxide (124 μl, 396 μmol) were added and the reaction was allowed tostir for another 48 h. before the reaction was quenched with water andsodium sulfite (1496 mg, 11872 μmol). The reaction was allowed to stirfor 15 min and then extracted with EtOAc (3×). The combined organicswere washed with HCl (1 N), sodium bicarbonate, brine and dried oversodium sulfate. The dried solution was passed through a plug of silicagel and concentrated to give 102 mg of a colorless oil

Step 7: (R)-tert-butyl3,4-bis(tert-butyldimethylsilyloxy)-1-fluoro-1-phenylbutan-2-ylcarbamate

To a 500 mL RBF containing tert-butyl(1S,2R)-1-fluoro-3,4-dihydroxy-1-phenylbutan-2-ylcarbamate (98.00 mg,327 μmol) was added DCM (5 mL) and the mixture was allowed to stir at 0°C. for 5 min. At this time, TEA (274 μl, 1964 μmol) andtert-butyldimethylsilyl triflate (188 μl, 818 μmol) was added to themixture via syringe. The reaction was allowed to stir for 30 min andthen queched with sodium bicarbonate (50 ml, sat). The aq. layer wasextracted with DCM (3×25 ml). The combined organics were washed withbrine, dried with sodium sulfate and passed through a plug of silica geland concentrated to give 203 mg of a yellow oil that was taken directlyto the next step.

Step 8: (R)-tert-butyl3-(tert-butyldimethylsilyloxy)-1-fluoro-4-hydroxy-1-phenylbutan-2-ylcarbamate

To a plastic bottle containing (R)-tert-butyl3,4-bis(tert-butyldimethylsilyloxy)-1-fluoro-1-phenylbutan-2-ylcarbamatewas added 10 ml THF, 3 ml pyridine, 1 ml HF-pyr at 0° C. The mixture wasstirred for 6 h and then carefully quench with sodium bicarbonate. Theaq. layer was extracted with DCM (4×25 ml). The combined organics werewashed with brine, dried with sodium sulfate, filtered, concentrated andthe crude purified on a 40 g ISCO column to give 225 mg of the titlecompound.

Step 9:N-((1S,2R)-1-fluoro-3-hydroxy-4-((S)-6-neopentyl-3′,4′-dihydrospirolcyclobutane-1,2′-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2-yl)acetamide

The title compound was prepared using procedures analogous to thosedisclosed in U.S. patent application Ser. No. 11/595,187 whichdisclosure is hereby incorporated by reference herein in its entirety.More particularly, the title compound was prepared using the Dess-Martinoxidation, reductive amination, deprotection and amide formationprocedures described both therein and herein.

Example 43N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[3,2-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide

The title compound was prepared according to a procedure analogous tothat described in Example 42 above. MS m/z: 514.2 (M+H).

Example 44N-((1S,2R)-3-(((4′S)-6′-((1,1-difluoroethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

The title compound was prepared according to a procedure analogous tothat described in Example 42 above. MS m/z: 494.4 (M+H).

Example 45N-((1S,2R)-3-(((4′S)-8-amino-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(1,3-benzodioxol-5-ylmethyl)-2-hydroxypropyl)-2-(methyloxy)acetamide

To a flame-dried microwave vial under Ar gas was added‘N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide(350 mg, 610 μmol), Pd2 dba3 (112 mg, 122 μmol), and DavePhos (106 mg,268 μmol). The vial was purged with N₂ 5×, then THF (5.0 mL), and LiHMDS(5487 μl, 5487 μmol) were added. The vial was sealed and heated in amicrowave at 110° C. for 10 min. The mixture was quenched with H₂O (8mL), and extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried (MgSO₄), and concentrated to give a brown oil. The crudeproduct was purified by reverse phase HPLC to give the title compound asan amorphous off-white solid. MS m/z: 555.2 (M+1).

Example 46N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-((2,2,2-trifluoroethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide

To a flame-dried microwave vial under Ar gas was addedN-((1S,2R)-1-((3-fluorophenyl)methyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide(100 mg, 182 μmol), cesium carbonate (357 mg, 1095 μmol), DavePhos (79mg, 201 μmol), palladium(II) acetate (41 mg, 182 μmol) were added andvial was flushed with N₂ 5×, then 2,2,2-trifluoroethanol (332 μl, 4561μmol) and toluene (1 mL) were added simultaneously. The reaction washeated in the microwave at 110° C. for 30 min. The reaction mixture wasfiltered through a small plug of silica gel, and the residue purified byreverse phase HPLC to give the title compound as a tan amorphous solid.MS m/z: 612.0 (M+1).

Example 47(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-((2,2,2-trifluoroethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)propanamide

To a flame-dried microwave vial under Ar gas was added(2R)—N-((1S,2R)-1-(4-fluorophenyl)methyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)propanamide(140 mg, 249 μmol), Pd₂ dba₃ (45.6 mg, 49.8 μmol), and DavePhos (43.1mg, 110 μmol). The vial was purged with N₂ 5×, then THF (1 mL),2,2,2-trifluoroethanamine (98.7 μl, 996 μmol), and LiHMDS (2242 μl, 2242μmol) were added. The vial was sealed and heated in a microwave at 110°C. for 10 min. The mixture was quenched with H₂O (8 mL), and extractedwith CH₂Cl₂ (3×20 mL). The combined organic layers were dried (MgSO₄),and concentrated to give a brown oil. The crude product was by reversephase HPLC to give the title compound as an amorphous off-white solid.MS m/z: 625.2 (M+1).

Example 48N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-((2-(methyloxy)ethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

To a flame-dried microwave vial under Ar gas was addedN-((1S,2R)-1-(4-fluorophenyl)methyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide(200 mg, 386 μmol), Pd2 dba3 (35.4 mg, 38.6 μmol), and DavePhos (33.4mg, 84.9 μmol). The vial was purged with N₂ 5×, then THF (1 mL),2-methoxymethanamine (133 μl, 1544 μmol), and LiHMDS (3474 μl, 3474μmol) were added. The vial was sealed and heated in a microwave at 110°C. for 10 min. The mixture was quenched with H₂O (1 mL), and filteredthrough a 0.2 um syringe filter. The filtrate was purified by reversephase HPLC to give the title compound as an amorphous off-white solid.MS m/z: 557.2 (M+1).

Example 49N-((1S,2R)-1-((3-Bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-((1,1-dimethylethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamideStep 1: (9H-Fluoren-9-yl)methyl(2S,3R)-1-(3-bromo-4-fluorophenyl)-4-((S)-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-(tert-butyldimethylsilyloxy)butan-2-ylcarbamate

In a 25-mL RBF,(S)-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine(0.038 g, 0.14 mmol) and (9H-fluoren-9-yl)methyl(2S,3S)-1-(3-bromo-4-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-4-oxobutan-2-ylcarbamate(prepared analogously to the corresponding N-Boc compound, except usingFmoc-Cl and Et₃N instead of Boc₂O, 0.089 g, 0.14 mmol) were dissolved inDCM (2.0 mL). Trimethoxymethane (0.40 ml, 3.6 mmol) was added, and thesolution was stirred at ambient temperature for 1 hr. Sodiumtriacetoxyborohydride (0.12 g, 0.58 mmol) was added, and the resultingsuspension was stirred at ambient temperature overnight. The mixture wasquenched with 10% aqueous sodium carbonate (8 mL). After 2 h, theaqueous phase was extracted with DCM (3×20 mL). The organic layers weredried over sodium sulfate and concentrated. The crude material waspurified through silica gel (20 mL) using 33% EtOAc-hexane to afford thetitle compound as a white foam. Found MS m/z 858/860 (M+1).

Step 2:N-((2S,3R)-1-(3-Bromo-4-fluorophenyl)-4-((S)-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-(tert-butyldimethylsilyloxy)butan-2-yl)acetamide

In a 25-mL RBF, the (9H-fluoren-9-yl)methyl(2S,3R)-1-(3-bromo-4-fluorophenyl)-4-((S)-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-(tert-butyldimethylsilyloxy)butan-2-ylcarbamate(0.073 g, 0.085 mmol) was dissolved in DMF (1.5 mL). The solution wascooled to 0° C. Pyrrolidine (0.018 ml, 0.21 mmol) was added and thereaction solution was warmed to ambient temperature. The reaction wasconcentrated on a rotovap, the crude residue was diluted with DMF (0.25mL), to which Hunig's base (0.060 mL, 0.34 mmol), and N-acetylimidazole(38 mg, 0.34 mmol) were added. The mixture was stirred at ambienttemperature overnight and concentrated. The residue was diluted withaqueous sodium bicarbonate (10 mL) and the aqueous phase was extractedwith EtOAc (3×20 mL). The organic phase was dried over sodium sulfateand concentrated. The crude material was purified by passing throughsilica gel (20 g; deactivated with TEA (2.0 mL)), eluting with DCM toafford the title compound. MS m/z 678/680 (M+1).

Step 3:N-((1S,2R)-1-((3-Bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-((1,1-dimethylethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide

In a 25-mL RBF, theN-((2S,3R)-1-(3-bromo-4-fluorophenyl)-4-((S)-6-tert-butoxy-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-(tert-butyldimethylsilyloxy)butan-2-yl)acetamide(0.050 g, 0.074 mmol) was dissolved in THF (2.0 mL). TBAF (1.0 M in THF,0.074 ml, 0.074 mmol) was added. After 1 h, the reaction wasconcentrated. The residue was purified by passing through silica gel (20g; deactivated with triethylamine (2.0 mL)), eluting with methanol-DCM(2.0 to 2.5%) to afford the title compound. MS m/z 564/566 (M+1).

Example 50N-((1S,2R)-((3-Bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)(methyl)amino)-2-hydroxypropyl)acetamide

In a 15-mL RB flask,N-((1S,2R)-1-((3-bromo-4-fluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide(0.027 g, 0.048 mmol) was dissolved in DCM (1.5 mL). Trimethylorthoformate (0.13 ml, 1.2 mmol) was added, followed by addition ofFormaldehyde (37%, 0.0089 ml, 0.12 mmol) as an aqueous solution. Themixture was stirred at ambient temperature for 2 h. Then sodiumtriacetoxyborohydride (0.036 g, 0.17 mmol) was added, and the mixturewas stirred at ambient temperature overnight. The reaction mixture wasquenched with 10% aqueous sodium carbonate (5 mL), stirred vigorouslyfor 2 h, and diluted with DCM (60 mL). The organic layer was separatedand extracted with dilute brine (5 mL), dried over sodium sulfate andconcentrated. The residue was purified by passing it through silica gel(20 g; deactivated with triethylamine (2.0 mL)), eluting with 95%EtOAc-hexane to provide the title compound. MS m/z 576/578 (M+1).

Example 51 N-((1S,2R)-3-(((1s,3R,4′S)-6′-(2,2-Dimethylpropyl)-3-(hydroxymethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamideStep 1:(S)—N-((2R,3S)-3-Amino-2-(tert-butyldimethylsilyloxo)-4-(4-fluorophenyl)butyl)-[(2,2-spirocyclobutyl-3′-cis-hydroxymethyl)]-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-amine

To a stirred solution of(S)—N-((2R,3S)-3-amino-2-(tert-butyldimethylsilyloxo)-4-(4-fluorophenyl)butyl)-[(2,2-spirocyclobutyl-3′-cis-methoxycarbonyl)]-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-amine(0.28 g, 0.5 mmol) in THF (5 ml) was added diisobutylaluminum hydride,1.0 m solution in hexanes (2 ml, 2 mmol) dropwise. The reaction mixturewas stirred at RT for about 2 h, then slowly quenched with Rochelle'ssalt vigorously stirred in 2 h. The reaction mixture was extracted withDCM (3×), dried over MgSO₄, concentrated to give the title compound as ayellow oil. MS (m+1): 586.8).

Step 2: N-((1S,2R)-3-(((1s,3R,4′S)-6′-(2,2-dimethylpropyl)-3-(hydroxymethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

The title compound was prepared by a procedure analogous to thatdescribed in Steps 2-3 of Example 49 above. MS: refer to Table I herein.

The following examples in Table I were prepared by methods and Stepsanalogous to those described in Examples 41-51 above. Provided also isthe mass spectral data and BACE enzyme and cell-based assay data (IC₅₀'sin uM) for each example, where available.

TABLE 1 BACE1 HEK FRET cell Observed assay assay Ex. No. Compound NameMS (uM (uM) 52 N-((1S,2R)-1-(1,3-benzodioxol-5- 576.3 0.042 0.103ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3,3-difluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 53N-((1S,2R)-3-((6′-(2,2-dimethylpropyl)- 550.3 0.011 0.0653,3-difluoro-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 54 N-((1S,2R)-3-((6′-(2,2-dimethylpropyl)- 532.30.003 0.066 3,3-difluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((phenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 55N-((1S,2R)-1-(1,3-benzodioxol-5- 546.3 0.02359 0.08303ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3,3-difluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 56 (2R)—N-((1S,2R)-1-((3- 535.4 0.00263 0.00305cyanophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 57N-((1S,2R)-1-((3-cyanophenyl)methyl)-3- 525.3 0.00294 0.0053(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 58(2R)—N-((1S,2R)-1-((3- 539.3 0.00575 0.00678cyanophenyl)methyl)-3-(((4′S)-6′-(2- fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 59N-((1S,2R)-3-(((4′S)-6′-(2,2- 582.4 0.36433 0.17123dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-(methyloxy)propanamide 60N-((1S,2R)-1-((3-cyanophenyl)methyl)-3- 624.4 0.02106 0.06315(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-1-cyclobutyl-4,4-dimethyl-5-oxo-3- pyrrolidinecarboxamide 61(2S)—N-((1S,2R)-1-((3- 575.3 0.00323 0.00965cyanophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-3,3,3-trifluoro-2-hydroxypropanamide 62 (2R)—N-((1S,2R)-1-((3- 575.30.00401 0.00983 cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-3,3,3-trifluoro-2-hydroxypropanamide 63(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 582.4 0.25803 0.12846dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-(methyloxy)propanamide 64(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 582.4 0.61719 0.07965dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-(methyloxy)propanamide 65N-((1S,2R)-3-(((4′S)-6′-(2,2- 582.4 0.03426 0.12727dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-(methyloxy)propanamide 661-cyclobutyl-N-((1S,2R)-3-(((4′S)-6′-(2,2- 635.4 0.04358 1.10647dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-4,4-dimethyl-5-oxo-3- pyrrolidinecarboxamide 671-cyclobutyl-N-((1S,2R)-3-(((4′S)-6′-(2,2- 635.4 0.4709 0.06253dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-5-oxo-3-pyrrolidinecarboxamide 68 (2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-568.3 0.04862 0.05526 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-hydroxypropanamide 69(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 568.3 0.03363 0.07835dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-3,3,3-trifluoro-2-hydroxypropanamide 70 (2R)—N-((1S,2R)-1-((4-chloro-3-566.3 0.05582 0.13796 fluorophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 71(2R)—N-((1S,2R)-1-((2,3- 550.3 0.0339 0.09268difluorophenyl)methyl)-3-(((4′S)-6′-(2- fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 72(2R)—N-((1S,2R)-1-((3-chloro-4- 566.3 0.02907 0.06051fluorophenyl)methyl)-3-(((4′S)-6′-(2- fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 73N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 568.3 0.01604 0.05314hydroxy-3-(((4′S)-6′-(3,3,3-trifluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 74(2R)—N-((1S,2R)-1-((3- 582.3 0.03045 0.09487fluorophenyl)methyl)-2-hydroxy-3- (((4′S)-6′-(3,3,3-trifluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 75(2R)—N-((1S,2R)-1-((4- 582.3 0.00668 0.01988fluorophenyl)methyl)-2-hydroxy-3- (((4′S)-6′-(3,3,3-trifluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 76N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 568.3 0.00368 0.01084hydroxy-3-(((4′S)-6′-(3,3,3-trifluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 77N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 572.3 0.00488 0.01597methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3-((trifluoromethyl)oxy)phenyl)methyl)-2- hydroxypropyl)acetamide 78N-((1S,2R)-3-(((4′S)-6′-(2,2- 514.3 0.00449 0.00763dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3- (methyloxy)phenyl)methyl)-2-hydroxypropyl)acetamide 79 N-((1S,2R)-3-(((4′S)-6′-(2,2- 544.3 0.006370.01477 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3- (methyloxy)phenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 80 N-((1S,2R)-3-(((4′S)-6′-(2,2-568.2 0.01231 0.12547 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3- (methyloxy)phenyl)methyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamide 81 N-((1S,2R)-3-(((4′S)-6′-(2,2-598.2 0.00251 0.01399 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3-((trifluoromethyl)oxy)phenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 82 N-((1S,2R)-3-(((4′S)-6′-(2,2-622.2 0.00283 0.52314 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluoro-3-((trifluoromethyl)oxy)phenyl)methyl)-2-hydroxypropyl)-2,2,2-trifluoroacetamide 83N-((1S,2R)-3-(((4′S)-6′-(acetylamino)- 471.1 0.59327 103′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 84 N-((4′S)-4′-(((2R,3S)-3-(acetylamino)-4-513.1 4.86752 10 (4-fluorophenyl)-2-hydroxybutyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-6′-yl)-2,2-dimethylpropanamide 85 N-((4′S)-4′-(((2R,3S)-3-(acetylamino)-4- 485.20.88988 10 (4-fluorophenyl)-2-hydroxybutyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-6′-yl)propanamide 86N-((4′S)-4′-(((2R,3S)-3-(acetylamino)-4- 499.1 7.46555 9.73297(4-fluorophenyl)-2-hydroxybutyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-6′-yl)-2-methylpropanamide 87 N-((1S,2R)-1-(1,3-benzodioxol-5- 551.1 0.117270.0828 ylmethyl)-3-(((4′S)-6′-(2-cyano-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 88N-((1S,2R)-1-(1,3-benzodioxol-5- 521.2 0.04846 0.01605ylmethyl)-3-(((4′S)-6′-(2-cyano-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 89 N-((1S,2R)-1-((3,5- 557.2 0.00495 0.05857difluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-4′- yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 90 N-((1S,2R)-1-((3,5- 527.2 0.01035 0.07474difluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-1′-oxo-3′,4′-dihydro-1′H-spiro[cyclopentane-1,2′-naphthalen]-4′-yl)amino)-2-hydroxypropyl)acetamide 91N-((1S,2R)-3-(((4′S)-6′-(2-cyano-2- 513.2 0.00442 0.00646methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5- difluorophenyl)methyl)-2-hydroxypropyl)acetamide 92 N-((1S,2R)-3-(((4′S)-6′-(2-cyano-2- 543.10.00325 0.00621 methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5-difluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 931,3-thiazol-5-ylmethyl ((1S,2R)-1-((3,5- 601.3 0.00495 0.0792difluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)carbamate 94 N-((1S,2R)-1-((3,5- 615.2 0.003 0.01707difluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-((1,3-thiazol-5-ylmethyl)oxy)acetamide 952,2-dichloro-N-((1S,2R)-1-((3,5- 571.2 0.00043 0.01667difluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 96 2-chloro-N-((1S,2R)-1-((3,5- 573.2 0.000230.04322 difluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2,2-difluoroacetamide 972,2-dichloro-N-((1S,2R)-1-((3,5- 585.3 0.01378 0.38469difluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)propanamide 98 N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-593 0.54043 0.76738 3-hydroxy-4-((S)-6-neopentyl-3,4-dihydrospiro[cyclobutane-1,2H- pyrano[2,3-b]pyridin-4-ylamino)butan-2-yl)-2,2-dichloropropanamide 99 N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-581.2 0.05934 0.31692 3-hydroxy-4-((S)-6-neopentyl-3,4-dihydrospiro[cyclobutane-1,2H- pyrano[2,3-b]pyridin-4-ylamino)butan-2-yl)-2-chloro-2,2-difluoroacetamide 100N-((2S,3R)-1-(benzo[d][1,3]dioxol-5-yl)- 579.1 0.01269 0.071413-hydroxy-4-((S)-6-neopentyl-3,4- dihydrospiro[cyclobutane-1,2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2- yl)-2,2-dichloroacetamide 101thiazol-5-ylmethyl (2S,3R)-1- 609.1 0.15924 1.85082(benzo[d][1,3]dioxol-5-yl)-3-hydroxy-4- ((S)-6-neopentyl-3,4-dihydrospiro[cyclobutane-1,2H- pyrano[2,3-b]pyridin-4-ylamino)butan-2-ylcarbamate 102 (R)—N-((2S,3R)-1-(3,5-difluorophenyl)-3- 546.2 0.00530.01063 hydroxy-4-((S)-6-neopentyl-3,4- dihydrospiro[cyclobutane-1,2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2- yl)-2-methoxypropanamide 103(S)—N-((2S,3R)-1-(3,5-difluorophenyl)-3- 546.2 0.0101 0.02684hydroxy-4-((S)-6-neopentyl-3,4- dihydrospiro[cyclobutane-1,2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2- yl)-2-methoxypropanamide 1042-chloro-N-((2S,3R)-1-(3,5- 537.1 0.00369 0.01875difluorophenyl)-3-hydroxy-4-((S)-6-neopentyl-3,4-dihydrospiro[cyclobutane- 1,2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-yl)acetamide 1052,2-dichloro-N-((1S,2R)-3-(((4′S)-6′-(2,2- 553.2 0.00406 0.02948dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 106 2,2-dichloro-N-((1S,2R)-3-(((4′S)-6′-(2,2-567.2 0.06691 0.83427 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2- hydroxypropyl)propanamide 1072-chloro-N-((1S,2R)-3-(((4′S)-6′-(2,2- 519.2 0.00507 0.02243dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 108 2-chloro-N-((1S,2R)-3-(((4′S)-6′-(2,2- 555.10.00506 0.09061 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2,2-difluoroacetamide 109N-((1S,2R)-3-(((4′S)-6′-(2,2- 498.2 0.07235 0.3186dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3-fluoro-2- methylphenyl)methyl)-2-hydroxypropyl)acetamide 110 N-((1S,2R)-1-fluoro-3-hydroxy-4-((S)-6-484.2 0.89655 0.8038 neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4-ylamino)-1- phenylbutan-2-yl)acetamide 111N-((1S,2R,3R)-1-fluoro-3-hydroxy-4-((S)- 484.2 0.01118 0.015866-neopentyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin-4-ylamino)-1-phenylbutan-2- yl)acetamide 112N-((1S,2R)-3-(((4′S)-6′-(2,2- 525.4 0.03043 0.00893dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 113 N-((1S,2R)-3-(((4′S)-8′-(dimethylamino)- 539.40.02646 0.49651 6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 114 N-((1S,2R)-3-(((1R,2S,4′S)-6′-(2,2- 500.01.5759 0.90893 dimethylpropyl)-2-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 115N-((1S,2R)-3-(((1S,2R,4′R)-6′-(2,2- 500.0 6.88019 5.4962dimethylpropyl)-2-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 116N-((1S,2R)-3-(((1R,2R,4′S)-6′-(2,2- 500.0 0.11718 0.14811dimethylpropyl)-2-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 117N-((1S,2R)-3-(((1S,2S,4′S)-6′-(2,2- 500.0 0.00785 0.03362dimethylpropyl)-2-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 118N-((1S,2R)-3-(((1S,2R,4′S)-6′-(2,2- 500.0 0.00911 0.028dimethylpropyl)-2-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 119N-((1S,2R)-1-(1,3-benzodioxol-5- 540.2 0.20318 0.12701ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 120N-((1S)-1-((1R)-2-(((4′S)-6′-(2,2- 446.3 0.74455 0.34266dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-hydroxyethyl)-3-buten-1-yl)-2-(methyloxy)acetamide 121 N-((1S,2R)-3-(((4′S)-6′-(2,2-496.4 0.02213 0.10212 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 122 N-((1S,2R)-3-(((4′S)-6′-(2,2- 514.3 0.007540.02305 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 123 N-((1S,2R)-3-(((4′S)-6′-(2,2- 514.2 3.715363.80719 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[3,2-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 124 N-((1S,2R)-1-(1,3-benzodioxol-5- 544.30.02863 0.11446 ylmethyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2- hydroxypropyl)acetamide 125N-((1S,2R)-1-(1,3-benzodioxol-5- 569.4 0.05703 0.01327ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 126N-((1S,2R)-1-(1,3-benzodioxol-5- 539.4 0.04841 0.0091ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 127 N-((1S,2R)-1-(1,3-benzodioxol-5- 574.30.02552 0.06784 ylmethyl)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 128N-((1S,2R)-3-(((4′S)-8′-(1-azetidinyl)-6′- 521.4 0.03316 0.016(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)acetamide 129N-((1S,2R)-3-(((4′S)-8′-amino-6′-(2,2- 555.2 0.119 0.03089dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(1,3- benzodioxol-5-ylmethyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 130N-((1S,2R)-1-(1,3-benzodioxol-5- 609.2 0.05413 0.05504ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(1-pyrrolidinyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 131(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 588.0 0.02679 0.37595ylmethyl)-3-(((4′S)-8′-chloro-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 132N-((1S,2R)-1-(1,3-benzodioxol-5- 510.0 0.02519 0.06605ylmethyl)-2-hydroxy-3-(((1s,3R,4′S)-3- methyl-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 133N-((1S,2R)-1-(1,3-benzodioxol-5- 540.0 0.03976 0.14283ylmethyl)-2-hydroxy-3-(((1s,3R,4′S)-3- methyl-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 134(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 554.0 0.02719 0.1923ylmethyl)-2-hydroxy-3-(((1s,3R,4′S)-3- methyl-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 135(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 597.2 0.06466 0.17531ylmethyl)-3-(((4′S)-8′-(dimethylamino)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 136(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 583.4 0.04114 0.01626ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 137(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 557.4 0.082 0.05753dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 138(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 571.2 0.1777 0.16206dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)(methyl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 139(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 557.4 0.04204 0.00899dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 140N-((1S,2R)-3-(((4′S)-6′-(2,2- 612.0 0.00775 0.11452dimethylpropyl)-8′-((2,2,2- trifluoroethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 141(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 625.2 0.31918 2.83803dimethylpropyl)-8′-((2,2,2- trifluoroethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 142N-((1S,2R)-1-(1,3-benzodioxol-5- 637.2 0.35042 1.94821ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-((2,2,2-trifluoroethyl)amino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 143N-((1S,2R)-3-(((4′S)-6′-(2,2- 611.4 0.01952 0.31407dimethylpropyl)-8′-((2,2,2- trifluoroethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 144N-((1S,2R)-3-(((4′S)-6′-(2,2- 581.4 0.09436 0.63375dimethylpropyl)-8′-((2,2,2- trifluoroethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 145(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 597.2 0.29755 0.77684ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)(methyl)amino)-2- hydroxypropyl)-2-(methyloxy)propanamide 146 N-((1S,2R)-3-(((4′S)-6′-((1,1- 494.3 0.421411.25253 difluoroethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 147N-((1S,2R)-3-(((4′S)-6′-(2,2- 543.2 0.04953 0.02315dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 148N-((1S,2R)-3-(((4′S)-6′-(2,2- 543.2 0.03868 0.00654dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 149N-((1S,2R)-3-(((4′S)-6′-(2,2- 557.2 0.04789 0.02717dimethylpropyl)-8′-((2- (methyloxy)ethyl)amino)-3′,4-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 150N-((1S,2R)-3-(((4′S)-6′-(2,2- 587.2 0.04793 0.02261dimethylpropyl)-8′-((2- (methyloxy)ethyl)amino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 151N-((1S,2R)-3-(((4′S)-6′-((1,1- 494.4 0.02047 0.08406difluoroethyl)oxy)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 152 (2S)—N-((1S,2R)-3-(((4′S)-6′-((1,1- 564.40.01064 0.0336 difluoroethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)-5-oxotetrahydro-2-furancarboxamide 153 N-((1S,2R)-3-(((4′S)-6′-(2,2-528.2 0.1996 0.15319 dimethylpropyl)-8′-methyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 154(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 528 0.01324 0.02805dimethylpropyl)-3′,4- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)propanamide 155 (2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 5280.04013 0.07595 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 156N-((1S,2R)-3-(((4′S)-6′-(2,2- 514 0.0277 0.04533 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-hydroxypropanamide 157(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 514 0.01515 0.02168dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-hydroxypropanamide 158 N-((1S,2R)-3-(((4′S)-6′-(2,2- 570 0.050430.24094 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2,3,3,3-tetrafluoropropanamide 159N-((1S,2R)-3-(((4′S)-6′-(3,3-difluoro-2,2- 520.3 0.01915 0.03628dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 160 N-((1S,2R)-3-(((4′S)-6′-(3,3-difluoro-2,2-550.3 0.00884 0.03915 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 161N-((1S,2R)-3-(((4S)-6-(2-cyano-2- 494.2 0.01125 0.01738methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 162N-((1S,2R)-3-(((4S)-6-(2-cyano-2- 524.3 0.04458 0.03105methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)acetamide 163 N-((1S,2R)-3-(((4′S)-6′-(2,2- 565.3 0.02690.03586 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-((2- (trifluoromethyl)-4-pyridinyl)methyl)propyl)-2- (methyloxy)acetamide 164N-((1S,2R)-3-(((5′S)-3′-(2,2- 482.3 0.06229 0.02051dimethylpropyl)-5′,8′-dihydro-6′H- spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 165N-((1S,2R)-3-(((5′S)-3′-(2,2- 518.3 0.10721 0.10928dimethylpropyl)-8′,8′-difluoro-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′- quinolin]-5′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 166N-((1S,2R)-3-(((4′S)-6′-(2,2- 595.3 0.01084 0.00985dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-((2- ((2,2,2-trifluoroethyl)oxy)-4-pyridinyl)methyl)propyl)-2- (methyloxy)acetamide 167N-((1S,2R)-1-(1,3-benzodioxol-5- 508.4 0.1248 0.06837ylmethyl)-3-(((5′S)-3′-(2,2- dimethylpropyl)-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′- yl)amino)-2-hydroxypropyl)acetamide168 N-((1S,2R)-1-(1,3-benzodioxol-5- 538.4 0.14886 0.21117ylmethyl)-3-(((5′S)-3′-(2,2- dimethylpropyl)-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′- yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 169 N-((1S,2R)-3-(((2R,4S)-6-(2,2- 517.3 0.019610.04544 dimethylpropyl)-8-fluoro-3,4,4′,5′-tetrahydrospiro[chromene-2,3′-furan]-4-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamideN-((1S,2R)-3-(((2S,4S)-6-(2,2- dimethylpropyl)-8-fluoro-3,4,4′,5′-tetrahydrospiro[chromene-2,3′-furan]-4-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 170N-((1S,2R)-1-(1,3-benzodioxol-5- 527.3 0.01249 0.05351ylmethyl)-3-(((4S)-6-(2,2- dimethylpropyl)-8-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide 171N-((1S,2R)-3-(((4S)-6-(2-cyano-2- 512.3 0.01585 0.02819methylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 172N-((1S,2R)-3-(((4S)-6-(2-cyano-2- 542.3 0.0186 0.04327methylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)acetamide 173 (2S)—N-((1S,2R)-3-(((4S)-6-(2-cyano-2- 556.30.03635 0.0546 methylpropyl)-8-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)propanamide 174 N-((1S,2R)-3-(((4S)-6-(2,2- 501.3 0.00720.05264 dimethylpropyl)-8-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 175(2S)—N-((1S,2R)-3-(((4S)-6-(2,2- 545.3 0.01725 0.22914dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)propanamide 176 N-((1S,2R)-1-(4-thiazolylmethyl)-3- 503.30.01054 0.01696 (((5′S)-3′-(2,2-dimethylpropyl)-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 177N-((1S,2R)-1-((3,4- 520.3 0.00217 0.00934difluorophenyl)methyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 178 N-((1S,2R)-1-(1,3-benzodioxol-5- 528.30.00839 0.01752 ylmethyl)-3-(((4′S)-6′-(3-fluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)acetamide 179N-((1S,2R)-3-(((4′S)-6′-((1R)-1-fluoro- 532.3 0.00549 0.018552,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 180 N-((1S,2R)-3-(((4′S)-6′-(3-fluoro-2,2- 484.30.00232 0.007 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)acetamide 181N-((1S,2R)-1-(1,3-benzodioxol-5- 558.3 0.01548 0.01757ylmethyl)-3-(((4′S)-6′-(3-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 182N-((1S,2R)-1-(1,3-benzodioxol-5- 528.3 0.00701 0.01598ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 183 N-((1S,2R)-1-(1,3-benzodioxol-5- 558.30.00863 0.01782 ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 184N-((1S,2R)-3-(((4′S)-6′-(3-fluoro-2,2- 514.3 0.00246 0.00645dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 185 N-((1S,2R)-1-(1,3-benzodioxol-5- 546.3 0.018490.02644 ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-fluoroacetamide 186(2R)—N-((1S,2R)-3-(((4′S)-6′-((1R)-1- 546.3 0.00776 0.0265fluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 187N-((1S,2R)-1-(1,3-benzodioxol-5- 531.4 0.02015 0.06346ylmethyl)-3-(((4S)-2-(2,2- dimethylpropyl)-6,6-dimethyl-4,5,6,7-tetrahydro-1-benzothien-4-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 188N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 530.3 0.06116 1.65509hydroxy-3-(((4′S)-6′-((1R)-1-hydroxy-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 189N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 530.3 0.87987 1.0028hydroxy-3-(((4′S)-6′-((1S)-1-hydroxy-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 190(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 572.4 0.02384 0.04323ylmethyl)-3-(((4′S)-6′-(3-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 191(2R)—N-((1S,2R)-1-((3- 554.3 0.12732 0.28135fluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide (2S)—N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- hydroxy-3-(((4′S)-6′-(3,3,3-trifluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 192(2R)—N-((1S,2R)-1-((4- 554.3 1.01716 2.02629fluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide ′(2S)—N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- hydroxy-3-(((4′S)-6′-(3,3,3-trifluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 193N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 540.3 0.20159 0.51799hydroxy-3-(((4′S)-6′-(3,3,3- trifluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 194(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 580.3 1.07076 1.52482ylmethyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3- trifluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 195N-((1S,2R)-1-(1,3-benzodioxol-5- 566.3 0.75439 0.62097ylmethyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3- trifluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 196N-((1S,2R)-1-(1,3-benzodioxol-5- 572.4 2.63943 3.9904ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-(methyloxy)propyl)-2- (methyloxy)acetamide 197N-((1S,2R)-1-(1,3-benzodioxol-5- 554.2 0.0209 0.02185ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 3-(methyloxy)propanamide 198N-((1S,2R)-3-(((4′S)-6′-((2S)-3,3-difluoro- 506 0.02896 0.032112-methylpropyl)-3′4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 199 N-((1S,2R)-3-(((4′S)-6′-((2R)-3,3- 5060.04516 0.05906 difluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 200N-((1S,2R)-3-(((4S)-6-(2-fluoro-2- 487.1 0.20616 0.37547methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 201N-((1S,2R)-3-(((4S)-6-(2-fluoro-2- 467.2 0.02011 0.07676methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 202N-((1S,2R)-3-(((4′S)-6′- 450.1 0.03417 0.06594(cyclopropylmethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)acetamide 203N-((1S,2R)-1-((7-bromo-1,3-benzodioxol- 589.2 0.00284 0.021085-yl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 204 N-((1S,2R)-1-((7-bromo-1,3-benzodioxol-619.6 0.09558 0.08245 5-yl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 205N-((1S,2R)-1-(2,3-dihydro-1,4- 524.2 0.02289 0.02294benzodioxin-6-ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 206 N-((1S,2R)-1-(2,3-dihydro-1,4- 554.2 0.022680.04249 benzodioxin-6-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 207N-((1S,2R)-1-((7-chloro-1,3-benzodioxol- 544.2 0.00663 0.014225-yl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 208 N-((1S,2R)-1-((7-chloro-1,3-benzodioxol-574.2 0.00641 0.00996 5-yl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 209(2R)—N-((1S,2R)-1-((7-chloro-1,3- 588.3 0.01217 0.01815benzodioxol-5-yl)methyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 210(2R)—N-((1S,2R)-1-((7-bromo-1,3- 631.6 0.16337 0.22406benzodioxol-5-yl)methyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 211N-((1S,2R)-1-((7-bromo-1,3-benzodioxol- 623.6 0.42345 0.311745-yl)methyl)-3-(((4′S)-6′-(2-fluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 212N-((1S,2R)-1-((4-chlorophenyl)methyl)-3- 530.2 0.00215 0.0314(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 213N-((1S,2R)-1-(cyclopropylmethyl)-3- 460.3 0.05695 0.07873(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 214N-((1S,2R)-1-((3-((difluoromethyl)oxy)- 580.2 0.00877 0.009034-fluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 215N-((1S,2R)-1-((3-chloro-4- 554.2 0.00705 0.02642fluorophenyl)methyl)-3-(((4′S)-6′-(3,3-difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 216 N-((1S,2R)-1-((4-chloro-3- 566.2 0.0160.02485 (methyloxy)phenyl)methyl)-3-(((4′S)-6′-(3,3-difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 217 N-((1S,2R)-3-(((4′S)-6′-(3,3-difluoro-2,2-520.2 0.00292 0.00298 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 218N-((1S,2R)-3-(((4′S)-6′-(3,3-difluoro-2,2- 550.2 0.00438 0.00525dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 219 (2R)—N-((1S,2R)-3-(((4′S)-6′-(3,3- 564.20.00508 0.00599 difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 220N-((1S,2R)-3-(((4S)-6-(2,2- 501.2 0.00405 0.01159dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-fluorophenyl)methyl)- 2-hydroxypropyl)acetamide 221N-((1S,2R)-3-(((4S)-6-(2,2- 531.2 0.01374 0.04442dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)acetamide 222 (2R)—N-((1S,2R)-3-(((4S)-6-(2,2- 545.2 0.004450.01273 dimethylpropyl)-8-fluoro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)propanamide 223 N-((1S,2R)-1-((2-((2,2-difluoroethyl)oxy)-564.2 0.00969 0.02979 4-pyridinyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide 224 N-((1S,2R)-1-((3,5- 519.20.00467 0.01935 difluorophenyl)methyl)-3-(((4S)-6-(2,2-dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide 225 N-((1S,2R)-1-((4-chloro-3-554.2 0.00922 0.02393 fluorophenyl)methyl)-3-(((4′S)-6′-(3,3-difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 226 N-((1S,2R)-3-(((4′S)-6′-(3,3-difluoro-2,2-538.2 0.00415 0.00527 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5- difluorophenyl)methyl)-2-hydroxypropyl)acetamide 227 (2R)—N-((1S,2R)-1-((4-chloro-3- 598.10.01509 0.03136 fluorophenyl)methyl)-3-(((4′S)-6′-(3,3-difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 228(2R)—N-((1S,2R)-3-(((4′S)-6′-(3,3- 582.2 0.00615 0.00756difluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5-difluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 229N-((1S,2R)-3-(((4S)-6-(2,2- 531.2 0.00819 0.08555dimethylpropyl)-8-fluoro-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((4-fluorophenyl)methyl)- 2-hydroxypropyl)-2-(methyloxy)acetamide 230 N-((1S,2R)-3-(((1s,3S,4′S)-6′-(2,2- 518 0.004240.01003 dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-fluoroacetamide 231N-((1S,2R)-3-(((1s,3S,4′S)-6′-(2,2- 500.3 0.00404 0.00304dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 232N-((1S,2R)-3-(((1s,3S,4′S)-6′-(2,2- 530.3 0.00234 0.00327dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 233N-((1S,2R)-1-((3,4- 548.3 0.00724 0.00733difluorophenyl)methyl)-3-(((1s,3S,4′S)-6′-(2,2-dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 234N-((1S,2R)-1-((4-chlorophenyl)methyl)-3- 546.3 0.00404 0.01349(((1s,3S,4′S)-6′-(2,2-dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 235N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 460 0.58114 0.45239hydroxy-3-(((1s,3S,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 236N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 460 5.1754 0.27036hydroxy-3-(((1r,3R,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 237N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 430 6.41509 2.4457hydroxy-3-(((1r,3R,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)acetamide 238N-((1S,2R)-1-(1,3-benzodioxol-5- 554 0.01841 0.03274ylmethyl)-3-(((1s,3R,4′S)-6′-(2,2- dimethylpropyl)-3-methyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 239(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 568 0.01785 0.03459ylmethyl)-3-(((1s,3R,4′S)-6′-(2,2- dimethylpropyl)-3-methyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 240N-((1S,2R)-1-(1,3-benzodioxol-5- 558 0.087 0.10808ylmethyl)-3-(((1s,3S,4′S)-6′-(2,2- dimethylpropyl)-3-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 241(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 572 0.00628 0.03357ylmethyl)-3-(((1s,3S,4′S)-6′-(2,2- dimethylpropyl)-3-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 242N-((1S,2R)-1-(1,3-benzodioxol-5- 486 23.885 1.16302ylmethyl)-2-hydroxy-3-(((1s,3S,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 243(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 500 36.0611 3.33333ylmethyl)-2-hydroxy-3-(((1s,3S,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 244N-((1S,2R)-1-(1,3-benzodioxol-5- 500.3 40 10ylmethyl)-2-hydroxy-3-(((1r,3R,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 245(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 500.3 40 10ylmethyl)-2-hydroxy-3-(((1r,3R,4′S)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 246N-((1S,2R)-1-(1,3-benzodioxol-5- 542 0.01347 0.01643ylmethyl)-2-hydroxy-3-(((1s,3S,4′S)-3-hydroxy-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 247N-((1S,2R)-1-(1,3-benzodioxol-5- 512 0.00677 0.01323ylmethyl)-2-hydroxy-3-(((1s,3S,4′S)-3-hydroxy-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 248(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 556 0.0172 0.03497ylmethyl)-2-hydroxy-3-(((1s,3S,4′S)-3-hydroxy-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 249N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 516.3 0.0065 0.01127hydroxy-3-(((1s,3S,4′S)-3-hydroxy-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 250(2R)—N-((1S,2R)-1-((4- 530 0.01281 0.02733fluorophenyl)methyl)-2-hydroxy-3- (((1s,3S,4′S)-3-hydroxy-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 251N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 486.3 0.00634 0.01179hydroxy-3-(((1s,3S,4′S)-3-hydroxy-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 252N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 518.3 0.02365 0.05381methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 253 (2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-532.3 0.03616 0.07442 methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 254N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 488 0.17778 0.15184methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 255 N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 518.30.18995 0.21603 methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 256(2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 532 0.22592 0.27359methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)propanamide 257 methyl (1s,3R,4′S)-4′-(((2R,3S)-3- 542.60.27072 0.37163 (acetylamino)-4-(4-fluorophenyl)-2-hydroxybutyl)amino)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridine]-3-carboxylate 258methyl (1r,3S,4′S)-4′-(((2R,3S)-3- 542.6 0.0389 0.09286(acetylamino)-4-(4-fluorophenyl)-2- hydroxybutyl)amino)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridine]-3-carboxylate 259 N-((1S,2R)-3-(((1s,3R,4′S)-6′-(2,2- 514.615.9694 3.33333 dimethylpropyl)-3-(hydroxymethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 260N-((1S,2R)-3-(((1s,3R,4′S)-3-cyano-6′- 509.6 0.09867 0.07023(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 261 N-((1S,2R)-3-(((1r,3S,4′S)-3-cyano-6′- 539.60.03891 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 262N-((1S,2R)-3-(((1r,3S,4′S)-3-cyano-6′- 509.6 0.04654(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 263 (1s,3R,4′S)-4′-(((2R,3S)-3-(acetylamino)-528.6 0.01072 0.97615 4-(4-fluorophenyl)-2- hydroxybutyl)amino)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridine]-3-carboxylic acid 264 N-((1S,2R)-1-(1,3-benzodioxol-5- 525.40.04223 0.06884 ylmethyl)-3-(((1r,3R,4′S)-6′-(2,2-dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((1s,3S,4′S)-6′-(2,2- dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- c]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 265 N-((1S,2R)-1-(1,3-benzodioxol-5- 508.49.60035 0.38833 ylmethyl)-2-hydroxy-3-(((4′S)-6′-(trifluoromethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)acetamide 266N-((1S,2R)-1-(1,3-benzodioxol-5- 538.4 7.47346 1.25325ylmethyl)-2-hydroxy-3-(((4′S)-6′- (trifluoromethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 267N-((1S,2R)-1-(1,3-benzodioxol-5- 555.6 0.03178 0.03142ylmethyl)-3-(((2s,3′S,4S)-6-(2,2- dimethylpropyl)-3′-hydroxy-3,4-dihydrospiro[chromene-2,1′-cyclobutan]- 4-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 268 (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 569.40.01872 0.01511 ylmethyl)-3-(((2s,3′S,4S)-6-(2,2-dimethylpropyl)-3′-hydroxy-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2- (methyloxy)propanamide 269(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 569.4 0.24224 0.10268ylmethyl)-3-(((2r,3′R,4S)-6-(2,2- dimethylpropyl)-3′-hydroxy-3,4-dihydrospiro[chromene-2,1′-cyclobutan]- 4-yl)amino)-2-hydroxypropyl)-2-(methyloxy)propanamide 270 N-((1S,2R)-3-(((4S)-6-bromo-8- 565.4 0.447870.15734 (ethylamino)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 271N-((1S,2R)-3-(((4′S)-6′-(2,2- 522.2 0.03867 0.10003difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 272 N-((1S,2R)-3-(((4′S)-6′-(2,2- 474.3 0.015080.01471 difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)acetamide 273N-((1S,2R)-3-(((4′S)-6′-(2,2- 504.3 0.01494 0.02648difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 274 N-((1S,2R)-3-(((4′S)-6′-(2,2- 492.2 0.029690.07265 difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 275 N-((1S,2R)-1-(1,3-benzodioxol-5- 518.20.08205 0.06383 ylmethyl)-3-(((4′S)-6′-(2,2- difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 276 N-((1S,2R)-1-(1,3-benzodioxol-5- 548.20.07601 0.08724 ylmethyl)-3-(((4′S)-6′-(2,2- difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 277N-((1S,2R)-3-(((4′S)-6′-(2,2- 492.3 0.00613 0.00936difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 278 N-((1S,2R)-3-(((4′S)-6′-(2,2- 522.2 0.006760.00822 difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 279 (2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 562.30.12609 0.10816 ylmethyl)-3-(((4′S)-6′-(2,2- difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 280N-((1S,2R)-3-(((4′S)-6′-(2,2- 558.2 0.01895 0.17452difluoropropyl)-3,3-difluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)acetamide 281N-((1S,2R)-1-(1,3-benzodioxol-5- 509.3 0.01125 0.05969ylmethyl)-3-(((4S)-6-(2,2- dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide 282N-((1S,2R)-1-(1,3-benzodioxol-5- 540.3 0.00613 0.01682ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 283N-((1S,2R)-1-(1,3-benzodioxol-5- 528.1 0.00751 0.019ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-fluoroacetamide 284N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 518.1 0.00265 0.00477methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 285 N-((1S,2R)-1-(1,3-benzodioxol-5- 544.20.05699 0.07385 ylmethyl)-3-(((4′S)-6′-(2-fluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 286N-((1S,2R)-1-((3,5- 536.2 0.00332 0.00599difluorophenyl)methyl)-3-(((4′S)-6′-(2- fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 287(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 554.2 0.0181 0.01414ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 288N-((1S,2R)-1-(1,3-benzodioxol-5- 564.1 0.05394 0.4552ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2,2,2-trifluoroacetamide 289methyl ((1S,2R)-1-(1,3-benzodioxol-5- 526.2 0.07753 0.19605ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)carbamate 290 N-((1S,2R)-1-(1,3-benzodioxol-5- 539.30.02313 0.05487 ylmethyl)-3-(((4S)-6-(2,2- dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]- 4-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide 291 N-((1S,2R)-1-((2,2-difluoro-1,3- 576.2 0.041410.38249 benzodioxol-5-yl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 292N-((1S,2R)-1-((2,2-difluoro-1,3- 546.3 0.03249 0.15887benzodioxol-5-yl)methyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 293 N-((1S,2R)-1-((2,2-dimethyl-1,3- 568.30.48381 0.33262 benzodioxol-5-yl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 294(2S)—N-((1S,2R)-1-(1,3-benzodioxol-5- 554.2 0.03349 0.06655ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 295(2R)—N-((1S,2R)-1-((2,2-difluoro-1,3- 590.2 0.09688 1.33365benzodioxol-5-yl)methyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 296(2S)—N-((1S,2R)-1-((2,2-difluoro-1,3- 590.2 0.10198 0.57544benzodioxol-5-yl)methyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 297N-((1S,2R)-3-(((4′S)-6′-(2,2- 528.3 0.00778 0.00853dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)acetamide N-((1S,2S)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)acetamide 298 N-((1S,2R)-3-(((4′S)-6′-(2,2- 558.3 0.009170.0071 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide N-((1S,2S)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 299(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 572.2 0.015 0.01219dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide (2R)—N-((1S,2S)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide 300(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 572.2 0.0571 0.13704dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide (2S)—N-((1S,2S)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide 301(2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2- 532.2 0.00781 0.00699methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)propanamide 302 N-((1S,2R)-3-(((4′S)-6′-(2,2- 558.1 0.005730.01152 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2-(methyloxy)acetamide 303(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 572.2 0.00901 0.02137dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide 304(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 572.2 0.0376 0.08825dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide 305N-((1S,2S)-3-(((4′S)-6′-(2,2- 528.3 0.03789 0.05795dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)acetamide 306 N-((1S,2R)-3-(((4′S)-6′-(2,2- 528.3 0.004280.00747 dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((7-fluoro-1,3- benzodioxol-5-yl)methyl)-2-hydroxypropyl)acetamide 307 N-((1S,2R)-1-(1,3-benzodioxol-5- 537.70.03131 0.06832 ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-oxopropanamide 308N-((1S,2R)-1-(1,3-benzodioxol-5- 551.8 0.02438 0.02091ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 3-oxobutanamide 309N-((1S,2R)-1-(1,3-benzodioxol-5- 544.2 0.02056 0.03996ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-chloroacetamide 310N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 536.3 0.05051 0.16554hydroxy-3-(((4′S)-6′-((1- (trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 311 N-((1S,2R)-1-((4-fluorophenyl)methyl)-2-566.3 0.05155 0.30733 hydroxy-3-(((4′S)-6′-((1-(trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 312N-((1S,2R)-1-(1,3-benzodioxol-5- 562.3 0.06168 0.19674ylmethyl)-2-hydroxy-3-(((4′S)-6′-((1-(trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 313 N-((1S,2R)-1-(1,3-benzodioxol-5- 592.30.15114 0.32669 ylmethyl)-2-hydroxy-3-(((4′S)-6′-((1-(trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 314N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 524.3 0.00419 0.0113hydroxy-3-(((4′S)-6′-((2S)-3,3,3-trifluoro- 2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 315N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 524.3 0.00611 0.00943hydroxy-3-(((4′S)-6′-((2R)-3,3,3-trifluoro- 2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 316N-((1S,2R)-2-hydroxy-1-(phenylmethyl)- 506.3 0.01363 0.049713-(((4′S)-6′-((2S)-3,3,3-trifluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 317N-((1S,2R)-2-hydroxy-1-(phenylmethyl)- 506.3 0.01969 0.027793-(((4′S)-6′-((2R)-3,3,3-trifluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 318N-((1S,2R)-2-hydroxy-1-(phenylmethyl)- 518.3 0.03468 0.085013-(((4′S)-6′-((1- (trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 319 N-((1S,2R)-2-hydroxy-1-(phenylmethyl)-548.3 0.05579 0.30864 3-(((4′S)-6′-((1-(trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 320N-((1S,2R)-1-(1,3-benzodioxol-5- 550.3 0.15511 0.12046ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2S)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 321N-((1S,2R)-1-(1,3-benzodioxol-5- 550.3 0.1339 0.06456ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2R)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 322N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 542.3 0.01089 0.03989hydroxy-3-(((4′S)-6′-((1R,2S)-1,3,3,3-tetrafluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 323N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 542.3 0.36519hydroxy-3-(((4′S)-6′-((1S,2S)-1,3,3,3-tetrafluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 324N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 542.3 0.01373 0.06325hydroxy-3-(((4′S)-6′-((1R,2R)-1,3,3,3-tetrafluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamideN-((1S,2R)-1-((3-fluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-((1S,2R)-1,3,3,3-tetrafluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide 325N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 554.3 0.00371 0.01366hydroxy-3-(((4′S)-6′-((2S)-3,3,3-trifluoro- 2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 326N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 554.3 0.00777 0.02709hydroxy-3-(((4′S)-6′-((2R)-3,3,3-trifluoro- 2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 327N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 566.3 0.00985 0.06044hydroxy-3-(((4′S)-6′-((1- (trifluoromethyl)cyclopropyl)methyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 328N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2- 482.3 0.00919 0.02298methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1- (phenylmethyl)propyl)-2- (methyloxy)acetamide329 N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 500.3 0.00326 0.00601hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 330(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 572.4 0.02213 0.04392ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 331(2S)—N-((1S,2R)-1-(1,3-benzodioxol-5- 572.4 0.05146 0.04463ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 332N-((1S,2R)-1-((4-fluorophenyl)methyl)-2- 500.3 0.01087 0.01894hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 333 (2R)—N-((1S,2R)-1-((4- 514.30.02895 0.04792 fluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 334N-((1S,2R)-1-(1,3-benzodioxol-5- 526.3 0.04803 0.06717ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 335(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 540.3 0.03827 0.07651ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 336(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 558.3 0.13482 0.40409ylmethyl)-3-(((4′S)-7′-fluoro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)propanamide 337N-((1S,2R)-1-(1,3-benzodioxol-5- 544.3 0.12042 0.53058ylmethyl)-3-(((4′S)-7′-fluoro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 338N-((1S,2R)-1-(1,3-benzodioxol-5- 514.3 0.10901 0.25233ylmethyl)-3-(((4′S)-7′-fluoro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 339 N-((1S,2R)-1-(1,3-benzodioxol-5- 580.30.0437 0.12558 ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2S)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 340(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 594.3 0.14791 0.09058ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2S)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 341N-((1S,2R)-1-(1,3-benzodioxol-5- 580.3 0.0595 0.1378ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2R)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 342(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 594.3 0.1754 0.34293ylmethyl)-2-hydroxy-3-(((4′S)-6′-((2R)-3,3,3-trifluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 343(2R)—N-((1S,2R)-1-((7-fluoro-1,3- 558.3 0.03441 0.04171benzodioxol-5-yl)methyl)-2-hydroxy-3- (((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 344(2R)—N-((1S,2R)-1-((3- 540.3 0.00894 0.0442fluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 345(2R)—N-((1S,2R)-1-((3- 547.3 0.02656 0.06089cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 346(2R)—N-((1S,2R)-1-((3,5- 558.3 0.01019 0.0471difluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide 347N-((1S,2R)-1-((3-cyanophenyl)methyl)-2- 533.3 0.01036 0.01923hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 348 N-((1S,2R)-1-((3,5- 544.30.00688 0.01817 difluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 349N-((1S,2R)-1-((3,5- 560.3 0.16608 0.1393difluorophenyl)methyl)-2-hydroxy-3- (((4′S)-6′-((1R)-2,2,2-trifluoro-1-hydroxyethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide N-((1S,2R)-1-((3,5-difluorophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-((1S)-2,2,2- trifluoro-1-hydroxyethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 350N-((1S,2R)-1-((3-fluorophenyl)methyl)-2- 526.3 0.00909 0.02453hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-(methyloxy)acetamide 351 N-((1S,2R)-1-((3-chloro-4-548 0.00275 0.01233 fluorophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 352N-((1S,2R)-1-((3-bromo-4- 592/594 0.00371 0.0176fluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)- 2-(methyloxy)acetamide 353N-((1S,2R)-1-((3-bromo-4- 564/566 0.12045 0.42392fluorophenyl)methyl)-3-(((4′S)-6′-((1,1- dimethylethyl)oxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide 354 N-((1S,2R)-1-((3-bromo-4- 576/578 4.775443.48843 fluorophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)(methyl)amino)-2- hydroxypropyl)acetamide 355N-((1S,2R)-3-((6′-(2,2-dimethylpropyl)-3′- 502.2 0.11726 0.11347fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 356 N-((1S,2R)-3-(((4′S)-6′-((1R)-1-fluoro- 5140.00317 0.00646 2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 357 N-((1S,2R)-3-(((3′S,4′R)-6′-(2,2- 502.3 13.266610 dimethylpropyl)-3′-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 358N-((1S,2R)-3-(((3′R,4′R)-6′-(2,2- 502.3 0.02239 0.35305dimethylpropyl)-3′-fluoro-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2- hydroxypropyl)acetamide 359 methyl((1S,2R)-1-(1,3-benzodioxol-5- 544.3 0.19857 0.2082ylmethyl)-3-(((4′S)-6′-((1R)-1-fluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-2-hydroxypropyl)carbamate 360 (2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 528.40.00311 0.00482 dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3- b]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)- 2-(methyloxy)propanamide 361(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2- 528.4 0.00658 0.00923dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2-(methyloxy)propanamide 362 N-((1S,2R)-1-(1,3-benzodioxol-5- 594.30.06014 0.12297 ylmethyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)acetamide 363(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5- 608.3 0.04901 0.1597ylmethyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoro-2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- (methyloxy)propanamide

The following compounds in Tables 2 and 3 are additional representativeexamples of Formulas I-IV provided by the present invention.

TABLE 2

Ex. No. R¹ B R⁸ X¹ S 364 CH₃—O—CH₂— benzyl-O— neopentyl NH cyclobutyl365 CH₃—S—CH₂— benzyl-S— isopropyl S cyclobutyl 366 CH₃—NH—CH₂—benzyl-NH— hydroxypropyl O cyclobutyl 367 CH₃—N(CH₃)—CH₂— benzyl-O—ethyl NH cyclopentyl 368 CH₃CH₂—O—CH₂— benzyl-S— butyl S cyclopentyl 369CH₃—O—CH₂CH₂— benzyl-NH— pentyl O cyclopentyl 370 CH₃—O—CH(CF₃)—3,5-dioxolylPh-CH₂— Cyclopropyl- SO₂ cyclopropyl methyl- 371CH₂(CF₃)—O—CH₂— 3,5-difluoroPh-CH₂— neopentyl N-Me cyclopropyl 372CH₃—S—CH₂— 3,5-dimethylPh-CH₂— isopropyl S cyclopropyl 373 CH₃CH₂—S—CH₂—3,5-dihydroxyPh- hydroxypropyl O cyclohexyl CH₂— 374 CH₃CH₂—NH—CH₂—3,5-dioxolylPh-CH₂— pentyl SO₂ cyclohexyl 375 (CH₃)₂NCH₂—O—3,5-difluoroPh-CH₂— Cyclopropyl- N-Et cyclohexyl CH₂— methyl- 376CH₃—O—CH₂— 3,5-dioxolylPh-CH₂— neopentyl NH cyclobutyl 377 CH₃—S—CH₂—3,5-difluoroPh-CH₂— isopropyl S cyclopentyl 378 CH₃—NH—CH₂—3,5-dimethylPh-CH₂— hydroxypropyl O cyclopentyl 379 CH₃—N(CH₃)—CH₂—3,5-dihydroxyPh- ethyl SO₂ cyclopentyl CH₂— 380 CH₃CH₂—O—CH₂—3,5-dioxolylPh-CH₂— butyl N-Me cyclopropyl 381 CH₃—O—CH₂CH₂—3,5-difluoroPh-CH₂— pentyl S cyclopropyl 382 CH₃—O—CH(CF₃)—3,5-dioxolylPh-CH₂— Cyclopropyl- O cyclopropyl methyl- 383CH₂(CF₃)—O—CH₂— 4-CH₃-phenyl neopentyl NH cyclohexyl

TABLE 3

Ex. No. R¹ B R⁸ X¹ S 384 CH₃—O—CH₂— benzyl-O— neopentyl NH 385CH₃—S—CH₂— benzyl-S— isopropyl S cyclobutyl 386 CH₃—NH—CH₂— benzyl-NH—hydroxypropyl O cyclobutyl 387 CH₃—N(CH₃)—CH₂— benzyl-O— ethyl NHcyclobutyl 388 CH₃CH₂—O—CH₂— benzyl-S— butyl S cyclopentyl 389CH₃—O—CH₂CH₂— benzyl-NH— pentyl O cyclopentyl 390 CH₃—O—CH(CF₃)—3,5-dioxolylPh-CH₂— Cyclopropylmethyl- SO₂ cyclopentyl 391CH₂(CF₃)-O—CH₂— 3,5-difluoroPh-CH₂— neopentyl N-Me cyclopropyl 392CH₃—S—CH₂— 3,5-dimethylPh-CH₂— isopropyl S cyclopropyl 393 CH₃CH₂—S—CH₂—3,5-dihydroxyPh- hydroxypropyl O cyclopropyl CH₂— 394 CH₃CH₂—NH—CH₂—3,5-dioxolylPh-CH₂— pentyl SO₂ cyclohexyl 395 (CH₃)₂NCH₂—O—3,5-difluoroPh-CH₂— Cyclopropylmethyl- N-Et cyclohexyl 396 CH₃—O—CH₂—3,5-dioxolylPh-CH₂— neopentyl NH cyclohexyl 397 CH₃—S—CH₂—3,5-difluoroPh-CH₂— isopropyl S cyclobutyl 398 CH₃—NH—CH₂—3,5-dimethylPh-CH₂— hydroxypropyl O cyclopentyl 399 CH₃—N(CH₃)—CH₂—3,5-dihydroxyPh- ethyl SO₂ cyclopentyl CH₂— 400 CH₃CH₂—O—CH₂—3,5-dioxolylPh-CH₂— butyl N-Me cyclopentyl 401 CH₃—O—CH₂CH₂—3,5-difluoroPh-CH₂— pentyl S cyclopropyl 402 CH₃—O—CH(CF₃)—3,5-dioxolylPh-CH₂— Cyclopropylmethyl- O cyclopropyl 403 CH₂(CF₃)—O—CH₂—4-CH₃-phenyl neopentyl NH cyclopropyl 404 CH₃—S—CH₂— phenyl isopropyl Scyclohexyl 405 CH₃—S—CH₂— phenyl isopropyl S cyclobutyl

The following examples provide a further understanding and appreciationof compounds of the present invention.

Example 406

Synthesis of(S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-amineStep 1: 2-bromo-5-(methoxymethoxy)pyridine

To a solution of 6-bromopyridin-3-ol (25 g, 144 mmol) in DMF (300 mL) at0° C. under N₂ is added portionwise NaH (5.7 g, 144 mmol) over 5 min.The reaction was stirred 1 h, then chloro(methoxy)methane (12 g, 144mmol) was added and the reaction stirred an additional 1 h at 0° C.Saturated sodium bicarbonate (500 mL) was added slowly and thesuspension stirred 30 min and warmed to rt. The solution was extractedwith EtOAc (3×400 mL), the combined organic layers washed with H₂O (500mL), saturated NaCl (500 mL), dried (Na₂SO₄), and concentrated in vacuoto give the title compound as a brown oil.

Step 2: 5-(methoxymethoxy)-2-neopentylpyridine

To a solution of 2-bromo-5-(methoxymethoxy)pyridine (30.5 g, 140 mmol)in THF (5 mL) at 0° C. under N₂ is addeddichloro-((bis-diphenylphosphino)ferrocenyl)-palladium(II) (4.88 g, 5.5mmol) followed by dropwise addition of neopentylmagnesium chloride (155mL, 155 mmol) over 2 min. After addition, the cooling bath was removedand the reaction stirred 3 h at rt. The reaction was cooled to 0° C. andsaturated NH₄Cl (500 mL) was added, and the aqueous layers extractedwith EtOAc (3×200 mL). The combined organic layers were washed withsaturated NaCl, dried (Na₂SO₄) and concentrated to give a red oil.Purification by vacuum filtration through a silica plug (9×7 cm, dryload, 10-20%% EtOAc/Hexanes) gives5-(methoxymethoxy)-2-neopentylpyridine as a light yellow oil.

Step 3: 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol

To a solution of 5-(methoxymethoxy)-2-neopentylpyridine (16.5 g, 79mmol) and in THF (200 mL)-78° C. is added tert-butyllithium (46 ml, 79mmol) (1.7 M in pentane) over 2 min via cannula. The reaction wasstirred at −78° C. 30 min, and acetaldehyde (11 ml, 197 mmol) was added.The reaction was stirred at −78° C. 10 min, then the reaction was warmedto rt and stirred 3 h. The reaction was quenched by addition ofsaturated aqueous NH₄Cl (400 mL), extracted with EtOAc (3×200 mL), thecombined organic layers washed with saturated NaCl (10 mL), dried(Na₂SO₄), and concentrated to give a orange oil, which was purified bychromatography on an ISCO (330 g SiO₂, 10%-50% EtOAc/Hexane) gives1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol as a clear, lightyellow oil.

Step 4: 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone

To a solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanol(24.4 g, 96.3 mmol) and sodium bicarbonate (32.4 g, 385 mmol) in CHCl₃(500 mL) at 0° C. was added Dess-Martin Periodinane (53.1 g, 125 mmol).The reaction was stirred 5 h, quenched with saturated aqueous Na₂SO₃(300 mL), extracted with CH₂Cl₂ (3×250 mL), the combined organic layerswashed with saturated NaCl (300 mL), dried (Na₂SO₄), and concentrated togive a yellow oil. Purification by ISCO (330 g SiO₂, 20% EtOAc/Hexane)gives 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone as a clear,colorless oil.

Step 5: 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone

A solution of 1-(5-(methoxymethoxy)-2-neopentylpyridin-4-yl)ethanone(21.6 g, 86 mmol) in (2:1:1) 5 M HCl: i-PrOH: THF (800 mL) was stirred 4h at rt. The mixture was concentrated to remove the THF and i-PrOH. Theresulting solution consisting of the product in aqueous HCl was quenchedby slow addition to a solution of saturated aqueous NaHCO₃ (500 mL)containing excess solid NaHCO₃ (50 g). The aqueous layer was extractedwith CH₂Cl₂ (3×250 mL), the organic layers combined and washed withsaturated aqueous NaCl (250 mL), dried (MgSO₄), and concentrated to give1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone as a brown oil.

Step 6:2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one

A mixture of 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone (14.8 g, 71mmol) (76894-11), Hünig's base (12 ml, 71 mmol), pyrrolidine (8.9 ml,107 mmol), and cyclobutanone (13 ml, 179 mmol) in toluene (300 mL) witha Dean-Stark trap was heated in a 140° C. oil bath for 2 h. The mixturewas cooled to rt, then diluted with EtOAc (25 mL), washed with H₂O,saturated aqueous NH₄Cl, saturated aqueous NaCl, dried (MgSO₄), andconcentrated. Purification by ISCO (120 g SiO₂, 10-20% EtOAc/Hexane)gives the title compound as a yellow solid.

Step 7:2,2-spirocyclobutyl-6-neopentyl-7-oxo-2,3-dihydropyrano[2,3-c]pyridin-4-one

2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one(5.00 g, 19 mmol) was dissolved in 100 ml CHCl₃ and cooled to 0° C.,mCPBA (10.0 g, 58 mmol) was added portionwise and the reaction wasstirred under N₂ and allowed to warm slowly to rt; stirring wascontinued for 17 h. The mixture was then cooled to 0° C., 1M NaOH (100mL) was added, and stirring was continued vigorously for 10 min. Themixture was extracted with CH₂Cl₂ (3×100 mL), the combined organiclayers washed with saturated sodium chloride (100 mL), dried (Na₂SO₄)and evaporated to give the title compound as a white solid.

Step 8: 8-chloro-2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one

2,2-spirocyclobutyl-6-neopentyl-7-oxo-2,3-dihydropyrano[2,3-c]pyridin-4-one.(5.3 g, 19 mmol) was taken up in phosphoryl trichloride (20 mL, 218mmol) and the mixture was heated to 80° C. for 2 h under N₂. Thereaction mixture was quenched by slow addition to vigorously stirredcold 10% aqueous NaCO₃ (300 mL), extracted with EtOAc (3×200 mL), thecombined organic layers were washed with saturated NaCl (200 mL), dried(Na₂SO₄), and concentrated to give a brown oil. Purification by ISCO(120 g SiO₂, 10% EtOAc/Hexane) gives the title compound as a lightyellow solid.

Step 9:(R)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ol

To a stirred solution of (s)-2-methyl-cbs-oxazaborolidine (1.7 ml, 1.7mmol) in THF (20 mL) at 0° C. is added borane-methyl sulfide complex (14ml, 28 mmol) followed by a solution of8-chloro-2,2-spirocyclobutyl-6-neopentyl-2,3-dihydropyrano[2,3-c]pyridin-4-one(4.90 g, 17 mmol) in THF (40 mL) dropwise via syringe pump over 2.8 h.The reaction was stirred an additional 30 min, then was quenched bydropwise addition (1 drop/10 sec) of 5 M HCl (25 mL) at 0° C., after 15mL HCl was added, bubbling had ceased and the addition rate wasincreased as the ice bath was removed. The reaction was stirred anadditional 2 h at rt. The reaction was recooled to 0° C. and neutralizedwith 5 M NaOH (27 mL). The mixture was then extracted with EtOAc (2×150mL), washed with saturated aqueous NaCl (200 mL), dried (MgSO₄), andconcentrated in vacuo. Purification by ISCO (120 g SiO₂, 20%EtOAc/Hexane) gives the title compound as a white foam.

Step 10:(S)-4-azido-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine

To a solution of(R)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ol(2.33 g, 7.9 mmol) in toluene (43 mL) is added diphenylphosphoryl azide(2.4 ml, 11 mmol) then 1,8-diazabicyclo(5.4.0)-7-undecene (1.6 ml, 11mmol). The reaction was stirred under N₂ at rt 4 days. The clear, lightyellow solution first turned into a yellow cloudy/opaque solution after10 min. Water (100 mL) was added and the reaction mixture extracted withEtOAc (3×100 mL). The combined organic layers were washed with saturatedNaCl (150 mL), dried (MgSO₄), and concentrated to give the titlecompound as a brown oil which was used in the next step withoutpurification.

Step 11:(S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-amine

To a solution of(S)-4-azido-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine(2.21 g, 6.9 mmol) in 10:1 THF/H₂O (44 mL) at 0° C. is added NaOH (3.0ml, 15 mmol) (5 N). After 5 min, trimethylphosphine (2.4 ml, 28 mmol)was added dropwise over 4 min. The reaction went from brown to pink topurple as N₂ evolution occurred. The ice bath was allowed to melt as thereaction warmed to rt and stirred a total of 15 h. The mixture wasre-cooled to 0° C. and 5 N HCl (25 mL) was added. The resulting mixturewas extracted with EtOAc (3×50 mL), the combined organic layers werewashed with 2.5 N HCl (2×25 mL). The combined aqueous layers were cooledto 0° C. and basified to pH 14 with 5 N NaOH (100 mL). The aqueous layerwas extracted with EtOAc (3×50 mL) the combined organic layers dried(Na₂SO₄), and concentrated to give the crude product as a viscous yellowoil. The combined organic layers were combined with the crude productfrom above and concentrated to give a crude yellow oil. Purification ofthe crude oil by flash chromatography (5×15 cm SiO₂, 0-10% MeOH/CH₂Cl₂gradient elution) gave the title compound as a yellow oil.

Example 407

Synthesis of (4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine-3-carboxylateStep 1: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate(0.096 g, 0.29 mmol) was dissolved in DMF (1 mL) with 1H-imidazole(0.026 g, 0.38 mmol) and tert-butylchlorodimethylsilane (0.053 g, 0.35mmol). The reaction was stirred 2 hrs, diluted with diethyl ether andwashed twice with water and once with brine. The organic layer was driedover magnesium sulfate and concentrated to furnish the title compound,which was used for the next step without purification.

Step 2: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate(0.100 g, 0.23 mmol) was dissolved in THF (2.5 mL) cooled to −78° C.n-Butyllithium (0.12 ml, 0.29 mmol) was added and the reaction wasstirred at −50° C. for 40 minutes followed by the addition ofiodomethane (0.018 ml, 0.29 mmol). After stirring 40 minutes thereaction was quenched with saturated ammonium chloride and extractedwith ethyl acetate. The combined organic layers were washed with water,brine, and dried over sodium sulfate to afford the title compound. MSm/z: 457.3 (M+1).

Step 3: (4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylthiazol-4-yl)methyl)oxazolidine-3-carboxylate(0.100 g, 0.219 mmol) was dissolved in THF (4 mL) and cooled to 0° C.Next, TBAF (0.547 ml, 0.547 mmol) was added dropwise and the reactionwas stirred 1 hr. and then quenched with saturated ammonium chloride anddiluted with EtOAc. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, brine, dried over sodium sulfate, and concentrated.Purification by column chromatography (2.5:1 Hexanes/EtOAc) afforded thetitle compound.

Example 408

Step 1: (S)-methyl2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)proanoate

Iodine (0.0140 g, 0.0553 mmol) was added to zinc (0.542 g, 8.29 mmol)and the solid mixture was heated under vacuum for 10 minutes. The flaskwas flushed with nitrogen three times and allowed to cool. DMF (0.5 mL,degassed with nitrogen) was added and the suspension was cooled to 0° C.and stirred while (R)-methyl 2-(tert-butoxycarbonyl)-3-iodopropanoate(1.82 g, 5.53 mmol) in DMF (2.8 mL) was added dropwise. The mixture wasstirred for 30 minutes at 0° C. and then allowed to come to RT for 30minutes. 1-Iodo-4-(trifluoromethyl)benzene (1.50 g, 5.53 mmol),tris(dibenzylideneacetone)dipalladium (0.101 g, 0.111 mmol), anddicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos) (0.182 g,0.442 mmol) were added. The flask was purged with nitrogen and heated at40° C. After 3 hours the reaction was allowed to cool and partitionedbetween EtOAc and an aqueous solution of ˜9:1 saturated ammoniumchloride/ammonium hydroxide. The aqueous layer was extracted with EtOAcand the combined organic layers were washed with water, brine, and driedover sodium sulfate. Concentration and purification by silica gelchromatography (6:1 Hexanes/EtOAc) afforded (S)-methyl2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate.

Step 2:(S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoic acid

(S)-Methyl2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoate (6.20 g,17.9 mmol) was dissolved in THF (180 mL) and cooled to 0° C. A 0.2 M ofaq. LiOH (89.3 ml, 17.9 mmol) was added dropwise and stirred 20 minutesbefore TLC analysis (2:1 Hexanes/EtOAc) showed no starting material. ThePH of the reaction was carefully adjusted to PH=8 with 1 N HCl. Theaqueous layer was washed with diethyl ether and the organics were backextracted with 1% aqueous sodium bicarbonate and the combined aqueouslayers were carefully brought to a PH=4 and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to afford(S)-2-(tert-butoxycarbonyl)-3-(4-(trifluoromethyl)phenyl)propanoic acid,which was used without further purification.

Example 409

(4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylpyridin-4-yl)methyl)oxazolidine-3-carboxylateStep 1: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate

The title compound was synthesized in manner analogous to that describedin Example 407, using (4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylatein the presence of TBSCl and imidazole, and was used without furtherpurification.

Step 2: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylpyridin-4-yl)methyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate(0.150 g, 0.344 mmol) was dissolved in THF (3.5 mL) cooled to 0° C.Acetyl chloride (0.0256 ml, 0.361 mmol) was added and the reaction wasstirred 30 minutes before METHYLMAGNESIUM BROMIDE (0.294 ml, 0.412 mmol)was added. The reaction was stirred 1 hr. at 0° C. and then warmed to RTand quenched with saturated ammonium chloride and diluted with EtOAc andwater. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were washed with a 9:1 aqueoussolution of saturated ammonium chloride/ammonium hydroxide, water,brine, and dried over sodium sulfate. The crude product was dissolved inisopropylacetate (4 mL) and heated to 50° C. before DDQ (0.117 g, 0.515mmol) was added. After 30 minutes the reaction was cooled and dilutedwith ethyl acetate and washed twice with saturated sodium bicarbonate,once with water, brine, and dried over sodium sulfate. The mixture waspassed through a plug of silica gel with 2:1 Hexanes/EtOAc andconcentrated to afford the title compound, MS m/z: 451.3 (100%, M+1)).

Step 3: (4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((2-methylpyridin-4-yl)methyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-((2-methylpyridin-4-yl)methyl)oxazolidine-3-carboxylate(0.083 g, 0.18 mmol) was dissolved in THF (2 mL) and cooled to 0° C.Next, TBAF (0.28 ml, 0.28 mmol) was added dropwise and the reaction wasstirred 1 hr. and then quenched with saturated ammonium chloride anddiluted with ethyl acetate. The layers were separated and the aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith water, brine, dried over sodium sulfate, and concentrated.Purification by column chromatography (19:1 DCM/MeOH) afforded the titlecompound, MS m/z: 337.2 (100%, M+1).

Example 410

Step 1: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

The title compound was synthesized in a manner analogous to Example 407,step 1 via (4S,5S)-tert-butyl4-((2-chloropyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylatein the presence of TBSCl and imidazole and was used without furtherpurification.

Step 2: (4S,5S)-tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

Dimethylethanolamine (0.128 ml, 1.27 mmol) was added to anhydroushexanes (1.4 L) and cooled to 0° C. N-BUTYLLITHIUM (2.5 M inhexanes)(1.02 ml, 2.55 mmol) was added dropwise and stirred for 30minutes before being cooled to −78° C. (4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(0.200 g, 0.425 mmol) in hexanes (1 mL) was added dropwise and thesolution was stirred for 1 hour at −78° C. to give a dark orangesolution. MeI (0.106 ml, 1.70 mmol) in THF (3.2 mL) was added dropwiseand the reaction was allowed to slowly warm to 0° C. and was quenchedwith saturated aqueous ammonium chloride. The reaction was diluted withethyl acetate and water and separated. The aqueous layer was extractedwith ethyl acetate and the combined organic layers were washed withwater, brine, dried over sodium sulfate, and concentrated to give thetitled compound which was used directly for the next step withoutpurification.

Step 3: (4S,5S)-tert-butyl4-((2-chloro-6-methylpyridin-4-yl)methyl)-5-(hydroxymethyl)-2,2-dimethyloxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloro-6-methylpyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(0.206 g, 0.425 mmol) was dissolved in THF (4 mL) and cooled to 0° C.TBAF (0.637 ml, 0.637 mmol) was added to the mixture dropwise and thereaction was stirred 1 hr and then quenched with saturated ammoniumchloride and diluted with EtOAc. The layers were separated and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with water, brine, dried over sodium sulfate, and concentrated.The crude material was purified by silica column chromatography (19:1DCM/MeOH) and then reverse phase HPLC to give the title compound. MSm/z: 371.3 (100%, M+1).

Example 411

(4S,5S)-tert-butyl5-(hydroxymethyl)-2,2-dimethyl-4-((1-methyl-2-oxo-1,2-dihydropyridin-4-yl)methyl)oxazolidine-3-carboxylate

(4S,5S)-Tert-butyl5-(hydroxymethyl)-4-((2-methoxypyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate(0.281 g, 0.797 mmol) was refluxed in methanol (17 mL) with MeI (0.0798ml, 1.28 mmol) for 48 hrs. Concentration and purification by silica gelchromatography (20:1 DCM/MeOH) afforded the titled compound along withrecovered starting material.

Example 412

(S)-methyl 3-(benzofuran-2-yl)-2-(tert-butoxycarbonyl)propanoate

The title compound was synthesized in a manner analogous to thatdescribed Example 408, using(R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate and 2-bromobenzofuran. (MS m/z:220.1 (100%, M-99).

Example 413

(S)-methyl2-(tert-butoxycarbonyl)-3-(2-(trifluoromethyl)pyrimidin-4-yl)propanoate

The title compound was synthesized in a manner analogous to thatdescribed Example 408, using (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate and4-chloro-2-(trifluoromethyl)pyrimidine.

Example 414

(S)-methyl2-(tert-butoxycarbonyl)-3-(2-(triisopropylsilyl)thiazol-5-yl)propanoate

The title compound was synthesized in a manner analogous to thatdescribed Example 408, using (R)-methyl2-(tert-butoxycarbonyl)-3-iodopropanoate and5-bromo-2-(triisopropylsilyl)thiazole (prepared according to Stangeland,Eric L.; Sammakia, Tarek, Use of Thiazoles in the Halogen DanceReaction: Application to the Total Synthesis of WS75624 B, Journal ofOrganic Chemistry (2004), 69(7), 2381-2385.). MS m/z: 443.3 (100%, M+1).

Example 415

Tert-butyl 3-oxopyrrolidine-1-carboxylate (20.0 g, 108 mmol) was addedto a solution of 1-(5-hydroxy-2-neopentylpyridin-4-yl)ethanone (7.58 g,37 mmol) (prepared according to a procedure described in WO2007061670),pyrrolidine (9.1 ml, 110 mmol), and HOAc (6.3 ml, 110 mmol) in ACN (131mL) and the reaction was heated to 75° C. After 12 hrs, the reaction wasallowed to cool. After diluting the reaction with ethyl acetate and 10%sodium carbonate, the layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith water, saturated ammonium chloride, brine, and dried over sodiumsulfate. The crude product was purified through a plug of silica gel(4:1 Hexanes/EtOAc) to afford the compounds above, as illustrated, as anapproximate 1:1 mixture of diastereomers. MS m/z: 375.2 (100%, M+1).

Example 416

Step 1

Hydroxylamine hydrochloride (0.900 g, 13.0 mmol) and Ketone (0.680 g,1.82 mmol) (prepared according to a procedure described in WO2007061670)were stirred in pyridine (15 mL) for 2 hours and then poured into waterand extracted with ether. The combined organic layers were washed withwater, brine, dried over magnesium sulfate, and concentrated to affordthe title compound.

Step 2

Added Ms-Cl (0.062 ml, 0.80 mmol) to a solution of TEA (0.094 ml, 0.67mmol) and product from step 1 above (0.260 g, 0.67 mmol) in ACN (6.5 mL)and stirred at ambient temperature until the starting material wasconsumed. The reaction was poured into water and extracted with ethylacetate. The organic layer was washed with water, then saturatedammonium chloride, brine, dried over sodium sulfate, and concentrated toafford the compound of Example 416, as illustrated.

Example 417

Step 1: 5-(methoxymethoxy)-2-(2-methylprop-1-enyl)pyridine

A solution of 2-chloro-5-(methoxymethoxy)pyridine (0.620 g, 3.6 mmol)and 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride (0.13 g,0.18 mmol) in THF (7 mL) was cooled to 0° C.2-methyl-1-propenylmagnesium bromide, (0.5 M in THF) (9.3 ml, 4.6 mmol)was added slowly and the reaction was allowed to stir 12 hrs at RT. Thereaction was quenched by the addition of a 10:1 aqueous sat. ammoniumchloride/ammonium hydroxide solution and extracted into ethyl acetate.The combined organic layers were washed with 10:1 aqueous sat. ammoniumchloride/ammonium hydroxide solution, water, brine, dried over sodiumsulfate and concentrated. The crude product was purified by filtrationthrough a plug of silica gel (2:1 Hexanes/EtOAc) to afford the titleproduct. MS m/z: 194.1 (100%, M+1).

Step 2: 2-(2,2-dimethylcyclopropyl)-5-(methoxymethoxy)pyridine

Diiodomethane (24.8 ml, 308 mmol) was added dropwise to a solution ofdiethylzinc (200 ml, 220 mmol) 1.1 M in toluene at 0° C. After theaddition, the solution was stirred at RT for 40 minutes and thenrecooled to 0° C. when5-(methoxymethoxy)-2-(2-methylprop-1-enyl)pyridine (21.3 g, 110 mmol) intoluene (150 mL) was added dropwise through an addition funnel. Thereaction was allowed to come to RT and was stirred 12 hrs before beingquenched at 0° C. by the addition of a 10:1 saturated ammoniumchloride/ammonium hydroxide aqueous solution. The layers were separatedand the aqueous layer was diluted with water and extracted into ethylacetate. The combined organic layers were washed with 10:1 saturatedammonium chloride/ammonium hydroxide aqueous solution, water, brine,dried over sodium sulfate, and concentrated. The crude product waspurified through a plug of silica (10:1 Hexanes/EtOAc) to afford thetitled compound. MS m/z: 208.2 (100%, M+1).

Step 3

The above depicted conversion of2-(2,2-dimethylcyclopropyl)-5-(methoxymethoxy)pyridine to the desireddepicted amine was prepared by a procedure analogous to that describedin WO2007061670.

Example 418

Synthesis of N-ethyl-N-isopropylpropan-2-aminium2-(difluoromethoxy)acetate

Benzyl 2-hydroxyacetate (3.2 ml, 22.2 mmol), sodium sulfate (0.63 g, 4.4mmol), and MeCN (34 ml) were placed in a 100 ml two-necked RBF fittedwith a magnetic stirrer, a dropping funnel and a refluxing condenser.2,2-Difluoro-2-(fluorosulfonyl)acetic acid (9.18 ml, 89 mmol) was thenadded with stirring at 45° C. After addition, the mixture was furtherstirred for 1 h at this temperature. The reaction mixture was pouredinto 10% aqueous sodium carbonate and was extracted with diethyl ether,the combined extracts were washed with 10% aqueous sodium carbonate,water, brine, dried over sodium sulfate, and concentrated. The crudematerial was purified by column chromatography (4:1 Hexanes/EtOAc) toafford the intermediate benzyl 2-(difluoromethoxy)acetate which wasdissolved in EtOAc (34 mL). N-Ethyl-N-isopropylpropan-2-amine (0.561 ml,3.2 mmol) was added and after degassing with nitrogen, palladium oncarbon (0.680 g, 0.64 mmol) was added. The reaction was purged withhydrogen and stirred under 50 PSI of hydrogen for 24 hours. The degassedreaction was filtered through a pad of Celite and concentrate to affordthe titled product as the amine salt which was used directly forsubsequent reaction steps without further purification.

Example 419

Synthesis ofN-[(4′S)-6′-((R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-[2H]pyrano[2,3-b]pyridin]-4′-yl]-4-amineandN-[(4′S)-6′-((S)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-[2H]pyrano[2,3-b]pyridin]-4′-yl]-4-amineStep 1: 2,2-dimethylcyclopropylboronic acid

Sodium periodate (2.23 g, 10.4 mmol) was added to a RT solution of2-(2,2-dimethylcyclopropyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.680 g, 3.47 mmol) (Prepared according to a procedure described inSynthesis, 8, pg 605-609, 1991) in THF/H₂O (4:1, 30 mL). The mixture wasstirred 5 minutes when HCl (2N) (1.14 ml, 2.29 mmol) was added. Afterstirring for 12 h the reaction was diluted with water and extracted withethyl acetate. The combined organic extracts were washed with water,brine, dried over sodium sulfate, and concentrated in vacuo to affordthe title compound which was used without further purification.

Step 2

N-[(4′S)-6′-((R)-2,2-Dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-[2H]pyrano[2,3-b]pyridin]-4′-yl]-N-2-propen-1-yl-,1,1-dimethylethyl ester carbamic acid andN-[(4′S)-6′-((S)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-[2H]pyrano[2,3-b]pyridin]-4′-yl]-N-2-propen-1-yl-,1,1-dimethylethyl ester carbamic acid and Pd(OAc)₂ (0.428 g, 1.91 mmol)and tricyclohexylphosphine (1.07 g, 3.81 mmol) were added to a solutionof 2,2-dimethylcyclopropylboronic acid (3.26 g, 28.6 mmol),N-[(4′S)-6′-bromo-3′,4′-dihydrospiro[cyclobutane-1,2′-[2H]pyrano[2,3-b]pyridin]-4′-yl]-,1,1-dimethylethyl ester carbamic acid (7.04 g, 19.1 mmol) (prepared by aprocedure analogous to that described in WO2007061670), and potassiumphosphate (14.2 g, 66.8 mmol) in 10:1 toluene/water (132 mL). Thereaction was refluxed at for 18 hours, cooled, diluted with ethylacetate and washed with 10:1 saturated ammonium chloride/ammoniumhydroxide and water. The aqueous layer was back extracted with ethylacetate and the combined organic layers were washed with water, brine,dried over sodium sulfate, and concentrated. The crude material waspurified by silica gel chromatography with 4:1 Hexanes/EtOAc to affordthe title compound as a 1:1 mixture of diastereomers. MS m/z: 359.3(100%, M+1). The diastereomers were further separated by HPLC to affordeach individual diastereomer.

Step 3: (S)-6-((R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospirolcyclobutane-1,2′-pyrano[2,3-b]pyridin-4-amine

The (R) diastereomer Boc protected product from step 2 (10.7 g, 29.8mmol) was stirred in a solution of TFA (46.0 ml, 597 mmol) and DCM (100mL) until LC/MS showed complete conversion to product. The solution wasconcentrated and the crude material was taken up in DCM and free-basedby washing with 1 N NaOH. Concentration of the organics after brine washand drying (sodium sulfate) afforded the titled compound. MS m/z: 259.2(100%, M+1).

Example 420

Synthesis of tert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(1H-imidazol-1-yl)butan-2-ylcarbamateStep 1:(S)—N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide

A solution of 2-bromothiazole (7.9 ml, 89 mmol) in 200 mL ether wascooled to −78° C. and treated with a solution of n-butyllithium (36 ml,89 mmol) (2.5N in hexanes). After stirring for 30 minutes the reactionmixture was slowly added to a cooled (−78° C.) suspension of(S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide(25.000 g, 59 mmol) in 100 mL ether. The reaction mixture was allowed tostir at −78° C. for one hour. The reaction mixture was quenched withMeOH and saturated NH4Cl solution. The organic solution was washed withwater, brine, dried over MgSO4 and concentrated in vacuo. Purificationof the crude residue by column chromatography gave(S)—N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide(24.81 g, 83% yield).

Step 2: tert-butyl(1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propylcarbamate

A solution of(S)—N-((1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propyl)-2-methylpropane-2-sulfinamide(16.000 g, 32 mmol) in 32 mL THF was cooled to −10° C. and was treatedwith a solution of HCl (4N in dioxane) (12 ml, 47 mmol). Almostimmediately a white solid precipitated, and an additional 32 mL of THFwas added to solubilize the solid. The reaction mixture was allowed tostir at −10° C. for 2 hours then was allowed to slowly warm to RTovernight. N,N-diisopropylethylamine (17 ml, 95 mmol) was added, and thereaction mixture was allowed to stir for 20 minutes. A solution ofdi-tert-butyldicarbonate (1N in THF) (35 ml, 35 mmol) was added, and thereaction mixture was allowed to warm to RT and stir overnight. Thereaction mixture was quenched with 6N NaOH and was allowed to stir for30 minutes. The reaction mixture was then diluted with ether, washedwith water then brine. The organics were dried over MgSO4 andconcentrated. Purification of the crude residue by column chromatographygave tert-butyl(1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propylcarbamate(6.15 g, 39% yield).

Step 3: tert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate

A solution of tert-butyl(1R,2S)-2,3-bis(tert-butyldimethylsilyloxy)-1-(thiazol-2-yl)propylcarbamate(6.150 g, 12.2 mmol) in 120 mL MeCN was treated with 4 A mol. sieves andwas allowed to stir at room temperature for 10 minutes. Methyltrifluoromethylsulfonate (1.62 ml, 14.7 mmol) was added, and thereaction mixture was allowed to stir for an additional 30 minutes. Thereaction mixture was then concentrated in vacuo. The crude residue wasdissolved in 100 mL MeOH, cooled to 0° C., and treated with NaBH₄ (1.39g, 36.7 mmol). The reaction mixture was allowed to warm to RT and stirfor an additional 20 minutes. The reaction mixture was thenconcentrated, diluted with EtOAc, filtered through celite and againconcentrated in vacuo. The residue was dissolved in 100 mL ACN and 20 mLwater and was treated with mercury(II)chloride (3.32 g, 12.2 mmol).After stirring for 30 minutes, an additional portion of NaBH₄ (1.39 g,36.7 mmol) was added, and the reaction mixture was allowed to stir foranother 30 minutes. The reaction mixture was quenched with saturatedNaHCO₃ solution and diluted with EtOAc. The crude reaction mixture wasthen washed with water then brine. The organic layer was dried overMgSO₄ and concentrated in vacuo. The crude residue was forced through ashort plug of silica eluting with ether. The filtrate was againconcentrated in vacuo yielding tert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate(5.33 g, 96.9% yield) with minor impurities.

Step 4: (S)-tert-butyl2-((S)-1,2-bis(tert-butyldimethylsilyloxy)ethyl)aziridine-1-carboxylate

A solution of tert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-hydroxybutan-2-ylcarbamate(1.025 g, 2.3 mmol) in 20 mL DCM was cooled to 0° C., treated withN,N-DIPEA (0.60 ml, 3.4 mmol) followed by Ms-Cl (0.18 ml, 2.3 mmol).After stirring at 0° C. for 2 hours, the reaction mixture wasconcentrated in vacuo and the crude residue was dissolved in 20 mL THF.KOt-Bu (0.51 g, 4.6 mmol) was added, and the reaction mixture wasallowed to stir at RT for 10 minutes. The reaction mixture was thendiluted with EtAOc, washed with water then brine. The organics driedover MgSO₄ and concentrated in vacuo. Purification of the crude residueby column chromatography gave (S)-tert-butyl2-((S)-1,2-bis(tert-butyldimethylsilyloxy)ethyl)aziridine-1-carboxylateas a clear oil.

Step 5: tert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(1H-imidazol-1-yl)butan-2-ylcarbamate

A solution of (S)-tert-butyl2-((S)-1,2-bis(tert-butyldimethylsilyloxy)ethyl)aziridine-1-carboxylate(0.740 g, 1.7 mmol) and 1H-imidazole (0.35 g, 5.1 mmol) in 3 mL toluenwas thoroughly degassed and treated with tributylphosphine (0.42 ml, 1.7mmol). The reaction mixture was heated to reflux and allowed to stir for3 hours. NaH (60% dispersion in mineral oil) (0.069 g, 2.9 mmol) wasadded and the reaction mixture was allowed to stir at 110° C. overnight.The reaction mixture was quenched with saturated NH4Cl solution anddiluted with EtOAc. The reaction mixture was washed with water thenbrine. The organics were dried over MgSO4 and concentrated in vacuo.Purification of the crude residue by column chromatography gavetert-butyl(2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(1H-imidazol-1-yl)butan-2-ylcarbamatewith tributylphosphine oxide as the major impurity. This material wasused without further purification.

Example 421

Synthesis ofN-((2S,3R)-4-((S)-2,2-spirocyclobutyl-8-morpholino-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide

A glass microwave reaction vessel was charged withN-((2S,3R)-4-((S)-2,2-spirocyclobutyl-8-chloro-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylamino)-1-(4-fluorophenyl)-3-hydroxybutan-2-yl)acetamide(118 mg, 228 μmol), Pd₂(dba)₃ (17.5 mg, 19 μmol), and DavePhos (26.9 mg,68 μmol). The vessel was purged with N₂ for 5 minutes, then THF (1 mL),LHMDS (2.0 ml, 2050 μmol), and morpholine (0.10 ml, 1148 μmol) wereadded. The reaction mixture was stirred and heated in a BiotageInitiator at 100° C. for 10 minutes. The reaction was filtered through a0.2 multipor nylon membrane and purified by reverse-phase preparativeHPLC (Shimadzu) on a Phenomenex Gemini column (10 micron, C18, 110 Å,Axia, 100×50 mm) eluting at 100 mL/min with a linear gradient of 10%(v/v) to 60% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes.The desired fractions were poured into 10% Na₂CO₃ and extracted withCH₂Cl₂ (3×20 mL) to give the titled compound as a light yellow solid.

MS m/z: 569.2 (M+1).

Example 422

Synthesis of(4S)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutylchroman-4-amineStep 1:(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane

To a round bottomed flask was added(R)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ol (37.7 g, 140mmol), CH₂Cl₂ (600 mL), DIPEA (39.0 ml, 210 mmol) and an ice bath. Aftercooling for 20 minutes, TBS triflate (32.0 ml, 139 mmol) was added.After stirring for 45 minutes, the ice bath was removed and anadditional 6 mL of TBS triflate were added. After stirring for a further30 minutes, the reaction was washed with water (100 mL), HCl (1M, 200mL), and sat'd NaHCO₃ (100 mL). The organic layer was concentrated invacuo. The crude orange oil was taken up in hexane (100 mL) and elutedthrough a plug of silica gel (600 mL Frit) using 2% EtOAc/hexane to give(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane(51.05 g, 95.1% yield), as a colorless oil. The material was carriedforward without further characterization. MS m/z: 253.1 (M−H-OTBS).

Step 2:(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)propan-2-one

To a RBF was added MePhos (1.7 g, 4.7 mmol),dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (1.4 g, 2.0mmol), and THF (29 mL). The solution was degassed with N₂ for 20minutes. The solution was heated to 45° C. for 20 minutes, then allowedto cool to RT. To a separated 500 mL RBF was added(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane(15.0 g, 39 mmol), potassium phosphate (21.77 g, 103 mmol) (freshlyground) and degassed acetone, 99% (140 ml, 1904 mmol). The solution ofcatalyst and ligand were cannulated into the acetone solution and theentire reaction further degassed with N₂ for 20 minutes. The solutionwas then stirred at reflux. After 24 hours, the reaction was allowed tocool to RT and filtered through a cartridge of celite. The filtrate wasconcentrated in vacuo and adsorbed onto a plug of silica gel andchromatographed through a Redi-Sep® pre-packed silica gel column (120g), eluting with 0% to 5% EtOAc in hexane, to provide(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)propan-2-oneas a light yellow oil. MS m/z: 229.1 (M−H-OTBS).

Step 3:(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-ol

To a RBF was added(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)propan-2-one(4.97 g, 13.8 mmol) and THF (60 mL, anhydrous). The solution was cooledto 0° C. and treated with methylmagnesium chloride (5.50 ml, 16.5 mmol).The solution was allowed to warm to RT over 1 hour, then stirred at RTfor 2 hours. The reaction was then partitioned between EtOAc:water andthe resulting aqueous layer extracted with EtOAc (50 mL). The combinedorganic layers were washed with brine, dried over MgSO₄, andconcentrated in vacuo to give(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-olas a yellow oil that solidified. MS m/z: 245.2 (M−H-OTBS).

Step 4:(R)-1-(8-bromo-4-(tert-butyldimethylsilyloxy)-2,2-spirocyclo-butyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-ol

To a RBF was added(R)-1-(4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-ol(5.04 g, 13.4 mmol), sodium bromide (2.75 g, 26.8 mmol), acetone:water(1:1, 160 mL), and Oxone (8.23 g, 13.4 mmol). The reaction warmed about10° C. After 6 hours, the reaction was filtered and the filtrateextracted with EtOAc (2×50 mL). The combined organic layers wereconcentrated in vacuo and adsorbed onto a plug of silica gel andchromatographed through a Redi-Sepi®pre-packed silica gel column (80 g),eluting with 0% to 10% EtOAc in hexane, to provide(R)-1-(8-bromo-4-(tert-butyldimethylsilyloxy)-2,2-spirocyclo-butyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-olas a light yellow oil. MS m/z: 325.0 (M−H-OTBS).

Step 5:1-((4R)-4-(tert-butyldimethylsilyloxy)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutyl-chroman-6-yl)-2-methylpropan-2-ol

A glass microwave reaction vessel was charged with(R)-1-(8-bromo-4-(tert-butyldimethylsilyloxy)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-6-yl)-2-methylpropan-2-ol(1.30 g, 2.9 mmol), DMF:Water (9:1, 20 mL), cesium carbonate (4.6 g, 14mmol), copper(I) iodide (0.54 g, 2.9 mmol), 1H-imidazole (0.97 g, 14mmol), and N,N′-dimethylethane-1,2-diamine (0.31 ml, 2.9 mmol). Thereaction mixture was stirred and heated in a Biotage Initiator at 180°C. for 40 minutes. The reaction was set up in triplicate. The vials wereall poured into 150 mL of water. The aqueous solution was extracted withEtOAc (4×40 mL). The combined organic layers were filtered through acelite cartridge to remove an emulsion. The filtrate was washed withwater, brine, and concentrated in vacuo to give a brown oil. The oil wasadsorbed onto a plug of silica gel and chromatographed through aRedi-Sep® pre-packed silica gel column (40 g), eluting with 0% to 5%MeOH in CH2Cl2, to provide1-((4R)-4-(tert-butyldimethylsilyloxy)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutyl-chroman-6-yl)-2-methylpropan-2-olas a brown solid. MS m/z: 443.3 (M+1).

Step 6:1-((4R)-4-(tert-butyldimethylsilyloxy)-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazole

To a RBF was added1-((4R)-4-(tert-butyldimethylsilyloxy)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutyl-chroman-6-yl)-2-methylpropan-2-ol(2.94 g, 6.64 mmol), CH₂Cl₂ (80 mL), and a dry ice/iPrOH bath. Afterstirring for 15 minutes, DAST (1.75 ml, 13.3 mmol) was added. After 30minutes, TLC shows complete conversion. The cooling bath was removed andthe material poured into sat'd NaHCO₃ (25 mL). The aqueous layer wasextracted with CH₂Cl₂ (5 mL) and the combined organic layers wereconcentrated in vacuo. The crude product was adsorbed onto a plug ofsilica gel and chromatographed through a Redi-Sep® pre-packed silica gelcolumn (12 g), eluting with 0% to 20% EtOAc in CH2Cl2, to provide1-((4R)-4-(tert-butyldimethylsilyloxy)-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazoleas a brown oil, that solidified upon standing. MS m/z: 445.3 (M+1).

Step 7:(4R)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spiro-cyclobutylchroman-4-ol

To a RBF was added1-((4R)-4-(tert-butyldimethylsilyloxy)-6-(2-fluoro-2-methylpropyl)-2,2-spiro-cyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazole(1.6 g, 3.6 mmol), THF (40 mL), and an ice bath. After stirring for 15minutes, TBAF (4.0 ml, 4.0 mmol) was added. After 3 hours, LC-MS showscomplete conversion. The reaction was poured on to a plug of silica geland eluted with 50% EtOAc in CH2Cl2, to provide(4R)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spiro-cyclobutylchroman-4-olas a light yellow solid. This material was carried forward as is. MSm/z: 331.2 (M+1).

Step8:1-((4S)-4-azido-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazole

To RBF was added(4R)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spiro-cyclobutylchroman-4-ol(1.18 g, 3.57 mmol), toluene (4 mL), and an ice bath. After stirring for15 minutes, DPPA (1.08 ml, 5.00 mmol) was added, then DBU (0.748 ml,5.00 mmol). After 24 hours, LC-MS shows complete conversion. Thereaction was diluted with water (100 mL) and extracted with EtOAc (3×40mL). The combined organic layers were concentrated in vacuo and adsorbedonto a plug of silica gel and chromatographed through a Redi-Sep®pre-packed silica gel column (12 g), eluting with 0% to 40% EtOAc inhexane, to provide1-((4S)-4-azido-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazoleas a light golden oil.

MS m/z: 356.4 (M+1).

Step 9:(4S)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutylchroman-4-amine

To RBF was added1-((4S)-4-azido-6-(2-fluoro-2-methylpropyl)-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-8-yl)-1H-imidazole(1.11 g, 3.1 mmol), THF (100 mL), and a dry ice/iPrOH bath. Afterstirring for 15 minutes, LAH (12 ml, 12 mmol) was added over 30 minutes.LC-MS showed no progress. The solution was warmed to 0° C. via an icebath. After a further 30 min, the reaction is ˜75% complete (via LC-MS).After another hour, the reaction was cautiously quenched with sat'dRochelle's salt and the organic layer separated. The aqueous layer wasextracted with EtOAc (2×30 mL). The combined organic layers were washedwith brine, concentrated in vacuo, and adsorbed onto a plug of silicagel and chromatographed through a Redi-Sep® pre-packed silica gel column(12 g), eluting with 0% to 5% MeOH in CH2Cl2, to provide(4S)-6-(2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-2,2-spirocyclobutylchroman-4-amineas a light yellow oil. MS m/z: 330.4 (M+1).

Example 423

The amine chroman precursor of this compound was isolated as a byproductduring the synthesis of Example 422 above. The compound depicted abovewas made from this amine using procedures as described in WO2007061670.

Example 424

N-((2S,3S)-4-(2,2-spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ylamino)-3-hydroxy-1-((S)-tetrahydrofuran-3-yl)butan-2-yl)-2-methoxyacetamideStep 1:(S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(tetrahydrofuran-3-yl)butan-2-yl)-2-methylpropane-2-sulfinamide

A solution of azeotropically dried(S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide(2.3 g, 5 mmol) and 3-(iodomethyl)-THF (1 g, 7 mmol) in dry THF (10 mL)was brought to −78° C. followed by the dropwise addition oftert-butyllithium (6 mL, 11 mmol). A white precipitate was formed. Theresulting solution was stirred at −78° C. for 40 min, quenched with satNH₄Cl and extracted with EtOAc. The combined organics were washed withbrine, dried over Na₂SO₄, filtered, concentrated, and chromatographed onsilica gel using 0-5% EtOAc/hexanes to afford a colorless oil as(S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(tetrahydrofuran-3-yl)butan-2-yl)-2-methylpropane-2-sulfinamide.

Step 2: tert-butyl(2S,3S)-3(tert-butyldimethylsilyloxy)-4-hydroxy-1-((S)-tetrahydrofuran-3-yl)butan-2-ylcarbamateand tert-butyl(2S,3S)-3(tert-butyldimethylsilyloxy)-4-hydroxy-1-((R)-tetrahydrofuran-3-yl)butan-2-ylcarbamate

A solution of(S)—N-((2S,3S)-3,4-bis(tert-butyldimethylsilyloxy)-1-(tetrahydrofuran-3-yl)butan-2-yl)-2-methylpropane-2-sulfinamide(1.5 g, 3.0 mmol) in dry MeOH (30 mL) was brought to −20° C. followed bythe addition of 10% HCl (100 mL, MeOH/acetyl chloride) and the resultingmixture was stirred at −20 C for 1 h. The mixture was quenched with 10%Na₂CO₃ and extracted with DCM (8×). The combined organics were driedover Na₂CO₄, filtered, concentrated and colorless oil obtained wasdissolved in DCM (30 mL) followed by the addition of TEA (1.2 mL, 8.9mmol) and di-tert-butyldicarbonate (1.0 mL, 4.4 mmol). The reaction wasstirred at RT for 17 h. The mixture was concentrated and chromatographedon silica gel using 4:1 to 1:1 EtOAc/hexanes to afford a colorless oilastert-butyl(2S,3S)-3(tert-butyldimethylsilyloxy)-4-hydroxy-1-((S)-tetrahydrofuran-3-yl)butan-2-ylcarbamateAND Tert-butyl(2S,3S)-3(tert-butyldimethylsilyloxy)-4-hydroxy-1-((R)-tetrahydrofuran-3-yl)butan-2-ylcarbamate.

Step 3:N-((2S,3S)-4-(2,2-spirocyclobutane-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-4-ylamino)-3-hydroxy-1-((S)-tetrahydrofuran-3-yl)butan-2-yl)-2-methoxyacetamide

The titled compound was prepared from the product of step 2 according tothe procedure described in Example 42 herein.

Example 425

N-((2S,3R)-1-(3,5-difluorophenyl)-4-(6-((R)-2,2-dimethylcyclopropyl)-2,2-spirocyclobutane-8-(pyridine-4-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4-ylamino)-3-hydroxybutan-2-yl)-2-methoxyacetamide

To a microwave vial were addedN-((2S,3R)-4-(8-chloro-6-((R)-2,2-dimethylcyclopropyl)-2,2-spirocyclobutane-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4-ylamino)-1-(3,5-fidluorophenyl)-3-hydroxybutan-2-yl)-2-methoxyacetamide(0.43 g, 0.76 mmol), 4-pyridylboronic acid (0.14 g, 1.1 mmol),tetrakis(triphenylphosphine)palladium (0.13 g, 0.11 mmol), and potassiumcarbonate (0.14 ml, 2.3 mmol) and the mixture was purged with N₂followed by the addition of 1,4-dioxane (6 mL) and water (0.6 mL). Themixture was again purged with N₂ and heated in a microwave oven at 140°C. for 30 min. The mixture was filtered through celite, concentrated,and purified by HPLC to affordN-((2S,3R)-1-(3,5-difluorophenyl)-4-(6-((R)-2,2-dimethylcyclopropyl)-2,2-spirocyclobutane-8-(pyridine-4-yl)-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4-ylamino)-3-hydroxybutan-2-yl)-2-methoxyacetamideas a light yellow solid. MS m/z: 607.2 (M+1).

Example 426

N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1H-imidazol-1-yl)benzyl)-2-hydroxypropyl)acetamide

A 2-5 mL microwave vial was charged withN-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-bromo-4-fluoro-3-benzyl)-2-hydroxypropyl)acetamide(199 mg, 353 μmol), cesium carbonate (575 mg, 177 μmol), imidazole (360mg, 529 μmol), and copper iodide (67.0 mg, 353 μmol). The vial wascapped, and 10:1 dimethylformamide/water (2 mL) andN,N′-dimethylethane-1,2-diamine (38 μl, 35 μmol) were added in sequence.The vial was heated to 185° C. in a Biotage Initiator microwave reactorfor 30 min. The reaction mixture was cooled and filtered through celite.The filter pad was washed with dichloromethane (3×5 mL), and thefiltrate was evaporated. The residue was subjected to reverse-phase HPLC(0.1% TFA, 10-90% acetonitrile in water) to give the product (120 mg,bis-trifluoroacetate salt, 53% yield) as a clear glass. MS m/z=550.2[M+H]⁺. Calc'd for C₃₁H₄₁FN₅O₃: 550.3.

Example 427

(S)-tert-butyl2,2-spirocyclobutyl-6-neopentyl-8-(thiazol-2-ylamino)-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylcarbamate

A 25-mL Schlenk flask was charged with (S)-tert-butyl8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-ylcarbamate(266 mg, 674 μmol), thiazol-2-amine (202 mg, 202 μmol), sodium carbonate(100 mg, 943 μmol), tris(dibenzylideneacetone)dipalladium (62 mg, 67μmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (117 mg,202 μmol). The flask was evacuated and refilled with N₂ (g). Thisprocess was repeated twice. Ar (g)-degassed toluene (3.4 mL) was added,and the resulting solution was stirred for 10 min. Water (12 μl, 67μmol) was added, and the reaction vessel was sealed and heated in a 100°C. oil bath for 24 h. The mixture was then cooled to RT, diluted withTHF (5 mL), filtered through celite, and concentrated under reducedpressure. The residue was purified by chromatography on a 40-g Redi Sepsilica gel column with 5-50% EtOAc/hexanes to give the product as aclear oil. MS m/z=459.3 [M+H]⁺. Calc'd for C₂₄H₃₅N₄O₃S: 459.2.

Examples 428 and 429

Synthesis ofN-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(4-fluoro-3-(1H-imidazol-2-yl)phenyl)-3-hydroxybutan-2-yl)acetamide(428) andN-((2S,3R)-1-(3-(1H-imidazol-2-yl)phenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxybutan-2-yl)acetamide(429)

Two dry microwave vials were each charged separately withN-((2S,3R)-1-(3-bromo-4-fluorophenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-3-hydroxybutan-2-yl)acetamide(78.0 mg, 139 μmol), imidazole (142 mg, 2.08 mmol), KI (46.0 mg, 277μmol), palladium acetate (6.2 mg, 28 μmol), copper iodide (53.0 mg, 277μmol), and DMF (0.75 mL). Each vial was capped and evacuated until themixture bubbled, then was refilled with N₂ (g). This process wasrepeated two additional times. The vials were sonicated until the solidshad dissolved (3-5 min), resulting in a deep blue solution. Each vialwas heated to 185° C. for 10 min in a Biotage Initiator MicrowaveReactor. The reaction mixtures were cooled to RT, combined, and filteredthrough a pad of celite. The filter pad was washed with DCM (4×5 mL),and the filtrate was evaporated. The residue was purified first byreverse-phase HPLC (0.1% TFA in 10-90% ACN/water), then bysupercritical-CO₂ chromatography to give product 1 and product 2 aswhite powders. MS for Product 1 (Example 428) m/z=550.2 [M+H]⁺. Calc'dfor C₃₁H₄₁FN₅O₃: 550.3. MS for Product 2 (Example 429) m/z=532.2 [M+1]⁺Calc'd for C₃₁H₄₂N5O₃: 532.3.

Example 430

Synthesis of(2R,3S)-3-amino-1-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-4-(3-ethynylphenyl)butan-2-oltrihydrochloride Step 1: tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate

Tert-Butyl(2S,3S)-1-(3-bromophenyl)-3-(tert-butyldimethylsilyloxy)-4-hydroxybutan-2-ylcarbamate(2.09 g, 4.40 mmol) was concentrated under reduced pressure from DCM ina 50-mL RBF. The flask was filled with N₂ (g), then PdCl₂(PhCN)₂ (0.101g, 0.264 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.153 g,0.529 mmol), and copper iodide (33.6 mg, 0.176 mmol) were added. Theflask was evacuated and refilled with N₂ (g). This process was repeated3×, then a rubber septum was attached. Ar (g)-degassed dioxane (10 mL,)was added, and the flask was sonicated for 5 min to dissolve thestarting materials. Ethynyltrimethylsilane (0.915 ml, 6.61 mmol) anddiisopropylamine (0.942 ml, 6.61 mmol) were added in sequence, and theresulting black solution was stirred at RT for 4 h. The reaction mixturewas diluted with EtOAc and filtered through a pad of celite. Thefiltrate was evaporated, and the crude product was purified bychromatography on a 120-g Redi-Sep silica gel column, eluting with 5-40%ethyl acetate/hexanes to give tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamateas a brown oil.

Step 2: tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate

A RBF containing a solution of tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-hydroxy-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate(2.04 g, 4.15 mmol) in DCM (30 mL) was placed in an ice-bath for 10 min.Sodium bicarbonate (1.05 g, 12.4 mmol) and Dess-Martin Periodinane (2.29g, 5.39 mmol) were added in sequence, the ice-bath was removed, and thereaction was stirred for 2 h. The reaction mixture was diluted with a1:1 mixture of saturated sodium thiosulfate solution and brine (60 mL),and the resulting biphasic mixture was stirred vigorously for 2 min. Themixture was then extracted with DCM (3×30 mL), and the combined organicextracts were dried over sodium sulfate, filtered, and evaporated. Theresidue was purified by chromatography on a 120-g Redi-Sep column,eluting with 5-30% EtOAc/Hexanes to give tert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamateas a pale yellow oil.

Step 3: tert-butyl(2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(3-ethynylphenyl)-3-hydroxybutan-2-ylcarbamate

Trimethyl orthoformate (708 μl, 6.40 mmol) was added to a mixture oftert-butyl(2S,3S)-3-(tert-butyldimethylsilyloxy)-4-oxo-1-(3-(2-(trimethylsilyl)ethynyl)phenyl)butan-2-ylcarbamate(392 mg, 800 μmol) and(S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-amine(219 mg, 840 μmol) in DCM (16.0 mL, 800 μmol). The resulting mixture wasstirred for 40 min, then sodium triacetoxyborohydride (678 mg, 3.20mmol) was added and stirring was continued for 2 h. A saturated aqueoussolution of Rochelle's salt (55 mL) was added, and the resultingbiphasic mixture was stirred vigorously for 2 h. The reaction mixturewas extracted with DCM (3×25 mL), and the combined organic extracts werewashed with brine, dried over sodium sulfate, filtered, and evaporated.The residue was dissolved in THF (5 mL), and tetrabutylammonium fluoride(2.00 mL of a 1.0 M solution, 2.00 mmol) was added. The resulting orangesolution was stirred at RT for 16 h. The reaction mixture was thenpartitioned between water (15 mL) and ethyl acetate (10 mL). The layerswere separated, and the aqueous layer was extracted with ethyl acetate(2×10 mL). The combined organic extracts were dried over sodium sulfate,filtered, and evaporated. The crude product was purified bychromatography on an 80-g Redi-Sep silica gel column, eluting with 0-5%methanol/DCM to give tert-Butyl(2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(3-ethynylphenyl)-3-hydroxybutan-2-ylcarbamateas a white foam. MS m/z=548.4 [M+H]⁺. Calc'd for C₃₃H₄₆N₃O₄: 548.4.

Step 4:(2R,3S)-3-amino-1-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-4-(3-ethynylphenyl)butan-2-oltrihydrochloride

To an ice-cold (0° C.) solution of tert-butyl(2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(3-ethynylphenyl)-3-hydroxybutan-2-ylcarbamate(385 mg, 703 μmol) in MeOH (3.5 mL) was added HCl (8.79 mL of a 4.0 Msolution in dioxane, 35.1 mmol) over 2 min. The resulting yellowsolution was warmed to RT and stirred for 45 min. After this time, thesolution was concentrated under reduced pressure to give(2R,3S)-3-Amino-1-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-4-(3-ethynylphenyl)butan-2-oltrihydrochloride as a white solid. MS m/z=448.3 [M+H]⁺. Calc'd forC₂₈H₃₈N₃O₂: 448.2.

Example 431

(S)-2,2-spirocyclobutyl-6-neopentyl-N8-phenyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-4,8-diamine

A dry 2-mL microwave vial was charged with(S)-8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-amine(186 mg, 631 μmol), DavePhos (109 mg, 278 μmol), andtris(dibenzylideneacetone)dipalladium(0) (116 mg, 126 μmol). The vesselwas sealed and purged with N₂(g). THF (3 mL) was added, followed byaniline (345 μl, 3785 μmol). Lithium bis(trimethylsilyl)amide (3785 μlof 1.0 M solution in THF, 3785 μmol) was added dropwise over 25 secondsto give a dark purple solution. This mixture was heated in a BiotageInitiator microwave reactor at 110° C. for 10 min. The reaction mixturewas diluted with 2N HCl solution (aq., 20 mL) and washed with DCM (1×20mL, 2×10 mL). The DCM layers were combined and extracted with water (10mL). The aqueous layers were combined and treated with 1N NaOH solution(to pH 13) and extracted with ethyl acetate (3×30 mL). The combinedorganic extracts were dried over MgSO₄, filtered, and evaporated. Theresidue was purified by chromatography using a 40 g Redi-Sep columneluting with DCM (2 min), then a gradient of 8% MeOH/0.8% NH₄OH/DCM over15 min, then 8% MeOH/0.8% NH₄OH/DCM for 2 min to give desired product(179.5 mg, 81%) as a tan foam. MS m/z=352.2 [M+H]⁺. Calc'd forC₂₂H₃₀N₃O: 352.2.

Example 432

N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-1-(4-fluoro-3-(furan-2-yl)phenyl)-3-hydroxybutan-2-yl)acetamide

A microwave vial was charged withN-((2S,3R)-1-(3-chloro-4-fluorophenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxybutan-2-yl)acetamide(151 mg, 292 μmol), X-Phos (28 mg, 58 μmol),tris(dibenzylideneacetone)dipalladium(0) (27 mg, 29 μmol),2-furanboronic acid (49 mg, 438 μmol), and sodium carbonate (186 mg,1752 μmol). The vessel was capped, evacuated, and refilled with N₂(g).This process was repeated 3×, then dioxane (2 mL) and water (2 mL) wereadded in sequence. The vessel was capped again and heated in a BiotageInitiator microwave reactor at 150° C. for 30 min. The reaction mixturewas diluted with DCM (20 mL) and water (10 mL). The layers wereseparated and the aqueous layer was extracted with DCM (10 mL). Theorganic layers were combined, washed with 0.5 N NaOH solution (aq., 20mL), washed with brine, dried over sodium sulfate, filtered, andevaporated. The residue was purified by reverse-phase HPLC (10-90%CH₃CN/H₂O with 0.1% TFA) to give the product TFA-salt as a white foam.MS m/z=549.2 [M+H]⁺. Calc'd for C₃₃H₄₂FN₂O₄: 549.3.

Example 433

N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-1-(3-fluoro-5-(pyridin-4-yl)phenyl)-3-hydroxybutan-2-yl)acetamide

A microwave vial was charged withN-((2S,3R)-1-(3-chloro-5-fluorophenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxybutan-2-yl)acetamide(170 mg, 329 μmol), sodium carbonate (209 mg, 1973 μmol),4-pyridineboronic acid (61 mg, 493 μmol), X-Phos (31 mg), andtris(dibenzylideneacetone)dipalladium(0) (30 mg, 33 μmol). Dioxane (2mL) and water (2 mL) were added, the flask was stoppered, and the vialwas heated in a Biotage Initiator microwave reactor at 150° C. for 30min. The mixture was diluted with DCM (25 mL) and water (10 mL), and thelayers were separated. The aqueous layer was extracted with DCM (10 mL),and the organic layers were combined. The combined organic layers werewashed with water (10 mL), washed with brine, dried over sodium sulfate,filtered, and evaporated to give an orange residue. The residue waspurified by reverse-phase HPLC (10-90% CH₃CN/H₂O with 0.1% TFA) to givethe product TFA-salt (228.9 mg, 88% yield) as a white foam. MS m/z=560.2[M+H]⁺. Calc'd for C₃₄H₄₃FN₃O₃: 560.3.

Example 434

N-((2S,3R)-3-hydroxy-4-((S)-6-isobutyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(4-(thiazol-2-yl)phenyl)butan-2-yl)-2-methoxyacetamide

A dry 2-5 mL microwave vial was charged withN-((2S,3R)-1-(4-chlorophenyl)-3-hydroxy-4-((S)-6-isobutyl-2,2-spirocyclobutyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-yl)-2-methoxyacetamide(300 mg, 581 μmol), X-Phos (553 mg),tris(dibenzylideneacetone)dipalladium(0) (532 mg, 581 μmol), and dioxane(4 mL). The mixture was sonicated for about one minute.2-(Tributylstannyl)thiazole (640 μl, 2035 μmol) was added, and the vialwas immediately heated in a Biotage Initiator microwave reactor at 150°C. for 30 min. The reaction mixture was diluted with DCM and filteredthrough celite. The filtrate was evaporated, and the residue waspurified via chromatography on a 40-g Redi-Sep column, eluting with 0-5%MeOH/DCM. The material thus obtained was further purified byreverse-phase HPLC (10-90% CH₃CN/H₂O with 0.1% TFA) to give the productTFA-salt as a white foam. MS m/z=565.2 [M+H]⁺. Calc'd for C₃₁H₄₁N₄O₄S:565.3.

Example 435

N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)-1-(3-fluoro-5-(thiazol-2-yl)phenyl)-3-hydroxybutan-2-yl)acetamide

N-((2S,3R)-1-(3-Chloro-5-fluorophenyl)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxybutan-2-yl)acetamide(150 mg, 290 μmol), X-Phos (276 mg), andtris(dibenzylideneacetone)dipalladium(0) (266 mg, 290 μmol) werecombined in a microwave tube, which was then sealed, evacuated, andrefilled with N₂(g). Dioxane (1.5 mL) and 2-(tributylstannyl)thiazole(274 μl, 870 μmol) were added in sequence, and the mixture was heated ina Biotage Initiator microwave reactor at 150° C. for 30 min. Thereaction mixture was filtered through celite, the celite pad was washedwith DCM, and the filtrate was evaporated. The residue was purified bychromatography on a 40-g Redi-Sep column eluting with 0%-10% MeOH/DCM.The material thus obtained was further purified by reverse-phase HPLC(10-90% CH₃CN/H₂O with 0.1% TFA) to afford the product TFA-salt as awhite foam. MS m/z=566.2 [M+H]⁺. Calc'd for C₃₁H₄₀FN₄O₃S: 567.3

Example 436

N-((2S,3R)-4-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-1-(4-fluoro-3-(thiazol-4-yl)phenyl)-3-hydroxybutan-2-yl)acetamide

N-((2S,3R)-1-(3-Chloro-4-fluorophenyl)-4-((S)-2,2-dimethyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ylamino)-3-hydroxybutan-2-yl)acetamide(154.6 mg, 298 μmol), X-Phos (284 mg), andtris(dibenzylideneacetone)dipalladium(0) (273 mg, 298 μmol) werecombined in a microwave tube, which was then sealed, evacuated, andrefilled with N₂(g). Dioxane (1.5 mL) and 4-(tributylstannyl)thiazole(335 mg, 895 μmol) were added in sequence, and the mixture was heated ina Biotage Initiator microwave reactor at 150° C. for 30 min. Thereaction mixture was filtered through celite, the celite pad was washedwith DCM, and the filtrate was evaporated. The residue was purified bychromatography on a 40-g Redi-Sep column eluting with 0%-10% MeOH/DCM.The material thus obtained was further purified by reverse-phase HPLC(10-90% CH₃CN/H₂O with 0.1% TFA) to afford the product TFA-salt as awhite foam. MS m/z=567.2 [M+H]⁺. Calc'd for C₃₂H₄₁FN₃O₃S: 566.3.

Example 437

(S)-8-bromo-2,2-spirocyclobutyl-6-neopentylchroman-4-amine Step 1:6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one

To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (21.0 g, 98 mmol)in CH₃CN (200 mL) is added pyrrolidine (24 ml, 293 mmol) and HOAc (17ml, 293 mmol). The reaction was heated to 65° C. and stirred 9 h. Themixture was cooled to rt, concentrated in vacuo, then diluted with EtOAc(300 mL), and H₂O (400 mL). The organic layer was extracted and theaqueous layer extracted with EtOAc (2×200 mL). The combined organiclayers were washed with 10% Na₂CO₃ (200 mL), saturated NaCl (200 mL),dried (Na₂SO₄), and concentrated to give a brown oil. The crude productwas purified by ISCO (330 g SiO₂, 0-20% CH2Cl2/Hexanes) to give6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one as a yellow solidof 92% purity.

Step 2: (R)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ol

(S)-2-Methyl-CBS-oxazaborolidine (3.72 ml, 3.72 mmol) andborane-dimethyl sulfide (11.3 ml, 119 mmol) were dissolved in toluene(500 mL) and cooled to −10° C. A solution of6-bromo-2,2-spirocyclobutyl-2,3-dihydrochromen-4-one (19.85 g, 74.3mmol) in toluene (60 mL) was added dropwise via syringe pump over 1 h.The mixture was stirred at −10° C. for an additional 20 min the reactionwarmed to 0° C., and 2N HCl (100 mL) was added carefully. The phaseswere separated and the aqueous layer was extracted with EtOAc (3×150mL). The combined organic layers were dried (MgSO₄) and concentrated togive a clear oil. The crude product was purified by filtration through asilica plug, and used without purification in the next step.

Step 3:(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane

To a solution of(R)-6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-ol (20.0 g,74.3 mmol) in CH₂Cl₂ (300 mL) at rt is added TEA (15.5 ml, 111 mmol),then tert-butyldimethylsilyl triflate (17.1 ml, 74.3 mmol). The reactionis stirred at rt 45 min. The reaction is quenched with H₂O (200 mL) and1 N HCl (50 mL). The aqueous layer is extracted with EtOAc (2×200 mL)and the combined organic layers were dried (MgSO₄) and concentrated togive a purple oil. The crude product was purified by ISCO (330 g SiO₂,0-10% EtOAc/Hexane) to give(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilaneas a yellow oil.

Step 4:(R)-tert-butyl(2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)dimethylsilane

To a solution of(R)-(6-bromo-2,2-spirocyclobutyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane(10.0 g, 26 mmol), and PdCl₂(dppf)₂ (2 g, 3 mmol) in THF (100 ml) wasadded neopentylzinc(II) iodide (73 ml, 37 mmol). The reaction mixturewas stirred at rt overnight and then heated at 65° C. 2 h. The reactionwas cooled to rt and quenched with saturated NH₄Cl. The reaction wasextracted with EtOAc (3×), washed with brine, dried (MgSO₄), andconcentrated to give(R)-tert-butyl(2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)dimethylsilaneas a dark brown oil which was used in the next step withoutpurification.

Step 5:(R)-(8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane

A mixture of crude(R)-tert-butyl(2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)dimethylsilane(10 g, 27 mmol), sodium bromide (1.7 ml, 53 mmol), and Oxonemonopersulfate compound (15 ml, 27 mmol) in acetone/H₂O (200 ml, 1:1)was stirred at rt 2 h. The reaction was quenched with aqueous sodiumsulfite (4 eq., in 200 ml of H₂O) extracted with EtOAc (3×), dried(MgSO₄), and concentrated to give(R)-(8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilaneas a dark brown oil which was used in the next step withoutpurification.

Step 6:(R)-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ol

To a solution of(R)-(8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-yloxy)(tert-butyl)dimethylsilane(12 g, 26 mmol) in THF (50 ml) was added n-Bu₄NF (50 mL, 1.0 M in THF,50 mmol), and the mixture was stirred overnight at rt. To the reactionwas added H₂O, and the reaction solution was extracted with EtOAc (3×),the organic layers were dried over MgSO₄, concentrated, and purified byISCO (10% EtOAc/Hexanes) to give(R)-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-olas a light yellow oil.

Step 7:(S)-4-azido-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromene

To a solution of(R)-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-ol(6.65 g, 19.6 mmol) in CH₂Cl₂ (20 ml) at 0° C. was addeddiphenylphosphoryl azide (5.49 ml, 25.5 mmol) dropwise. After stirring15 min., DBU (3.84 ml, 25.5 mmol) was added dropwise and the reactionstirred at rt 24 h. H₂O was added and the reaction was extracted withether (3×). The combined organic layers were dried (MgSO₄) andconcentrated to give(S)-4-azido-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromeneas a brown oil which was used in the next step without purification.

Step 8:(S)-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromen-4-amine

To a solution of(S)-4-azido-8-bromo-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-chromene(7.14 g, 20 mmol), and 5 N aqueous NaOH (6 ml, 29 mmol) in THF (50 ml)at 0° C. was added trimethylphosphine (3 ml, 1.0M in THF, 29 mmol). Thereaction mixture was stirred 2 h at 0° C. The reaction was diluted withEtOAc, washed with H₂O, brine, and dried (MgSO₄). The filtrates wereconcentrated and purified by ISCO (2% MeOH/CH₂Cl₂) to give the titlecompound as a yellow oil.

Example 438

4-amino-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-8-carbonitrileStep 1: tert-butyl allyl(8-cyano-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)carbamate

To a solution of (S)-tert-butylallyl(8-chloro-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)carbamate(862 mg, 1982 μmol) in DMF (10 mL) under Ar is added zinc(II) cyanide(465 mg, 3963 μmol) and Pd(PPh₃)₄ (458 mg, 396 μmol). The mixture wassealed and stirred at 95° C. 19 h. The reaction was filtered through aplug of celite [CH₂Cl₂ wash (2×20 mL)], the filtrates diluted with water(10 mL) and extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried (Na₂SO₄), and concentrated to give a clear oil. The crudeproduct contained DMF which was removed by dissolving in EtOAc (10 mL)and extraction with H₂O (2×10 mL). The organic layer was dried (Na₂SO₄)and concentrated. The crude product was purified by ISCO (0-25%EtOAc/Hexane) to give racemized tert-butyl allyl(8-cyano-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)carbamateas a clear, colorless oil.

Step 2:4-amino-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridine-8-carbonitrile

To a 150 mL RBF with tert-butylallyl(8-cyano-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-c]pyridin-4-yl)carbamate(270 mg, 634 μmol) and CH₂Cl₂ (5 mL) is added TFA (587 μl, 7613 μmol)and the reaction was allowed to stir at rt 4 h. The reaction was dilutedwith CH₂Cl₂ (50 mL) washed with sat'd NaHCO₃ (2×100 mL) and the organiclayer degassed with Argon for 10 minutes. The degassed solution wastreated with 1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (307 mg, 1967μmol) and Pd(PPh₃)₄ (41.8 mg, 36.2 μmol) and stirred a rt for 18 h. Thereaction mixture was washed with NaOH (1N, 2×25 mL), then HCl (2N, 2×30mL). The acidic aqueous layer was then basified to pH 14 with NaOH (5N,30 mL) and extracted with DCM (3×50 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated in vacuo to give the title compoundas a clear, colorless oil.

Example 439

N-((1S,2R)-3-(((4S)-8-(2-(dimethylamino)-4-pyridinyl)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(3-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamidedi-TFA salts

A mixture ofN-((1S,2R)-3-(((4S)-8-(2-chloro-4-pyridinyl)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-(3-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamide(0.071 g, 0.09 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.008g, 0.009 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl(0.03 g, 0.09 mmol), dimethylamine (2.0M solution in THF, 0.2 ml, 0.3mmol), and lithium bis(trimethylsilyl)amide (1.0M solution in THF, 0.6ml, 0.6 mmol) was heated at 140° C. in 30 min. The mixture wasconcentrated, taken up in H₂O, extracted with DCM (3×), dried overMgSO₄, concentrated and purified by chromatography (Shimadzu system) togive the expected product with 95% purity as di-TFA salt. MS (M+1):633.3.

Example 440

(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-oxetanecarboxamideStep 1: (±)-oxetane-2-carboxylic acid

(±)-Oxetane-2-carboxylic acid was prepared from commercially available(±)-oxetan-2-ylmethanol by Jones oxidation, following the proceduredescribed in WO 2005-JP3755 20050304.

Step 2:(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-oxetanecarboxamide

The title compound was prepared by coupling (±)-oxetane-2-carboxylicacid with(2R,3S)-3-amino-1-((S)-2,2-spirocyclobutyl-6-neopentylchroman-4-ylamino)-4-(4-fluorophenyl)butan-2-olusing conditions described in Example 42. MS m/z 526 (M+1).

Example 441

(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4-fluorophenyl)methyl)-2-hydroxypropyl)-2-oxetanecarboxamide

The title compound was prepared by a method analogous to that describedin Example 440, using the other product isolated from Example 440,step 1. MS m/z 526 (M+1).

The following examples in Table 2 were prepared by methods and Stepsanalogous to those described in Examples 41-51, 421-436 and 439-441hereinabove. Provided also is the mass spectral data and additionaldata, including BACE enzyme and cell-based assay data (IC₅₀'s in uM),human and rat liver micorsomal data and CYP enzyme inhibition data,related to each example where available.

TABLE 2 BACE1 HEK FRET cell 3A4 2D6 Ex. Observed assay assay HLM RLMIC50 IC50 No IUPAC NAME MS (uM) (uM) (uL/min/mg) (uL/min/mg) (uM) (uM)442 (2R)—N-((1S,2R)-3-(((4′S)- 514.3 0.013 0.016 117.333 150.333 0.756.75 6′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- hydroxypropanamide 443 (2S)—N-((1S,2R)-1-(1,3- 597.20.065 0.175 190 232 benzodioxol-5-ylmethyl)- 3-(((4′S)-8′-(dimethylamino)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 444 (2R)—N-((1S,2R)-1-(1,3- 597.20.298 0.777 399 662 7.5 9.4 benzodioxol-5-ylmethyl)- 3-(((4′S)-8′-(dimethylamino)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 445 N-((1S,2R)-1-(1,3- 566.3 0.7540.621 24 121 0.2 4.1 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 446N-((1S)-2-(1,3- 584.3 6.319 10.000 150 106 0.2 1.2benzodioxol-5-yl)-1-((5R)- 3-((4′S)-6′-((1R)-1-fluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)-2-oxo-1,3- oxazolidin-5-yl)ethyl)-2-methoxyacetamide 447 N-((1S,2R)-1-(1,3- 572.4 2.639 3.990 14 14benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-((1R)-1-fluoro-2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- methoxypropyl)-2-methoxyacetamide 448 N-((1S,2R)-3-(((4′S)-6′- 580.4 0.106 0.153 79 0.11.8 (2,2-dimethylpropyl)-8′- (1H-imidazol-1-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 449N-((1S,2R)-3-(((4′R)-6′- 580.4 2.904 2.966 163 0.1 0.8(2,2-dimethylpropyl)-8′- (1H-imidazol-1-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 450(1S)—N-((1S,2R)-1-(1,3- 578.1 0.150 0.183 76 170 0.4 8.6benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-3- oxocyclopentanecarboxamide 451N-((1S,2R)-3-(((4′S)-6′- 597.3 0.019 0.271 248 682 0.6 9.4(2,2-dimethylpropyl)-8′- (1,3-thiazol-2-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 452N-((1S,2R)-1-(1,3- 542.3 0.016 0.039 45 174 0.3 2.1benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- fluoropropanamide 453 (2S)—N-((1S,2R)-1-(1,3- 566.40.022 0.037 25 125 0.2 3.6 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)tetrahydro-2-furancarboxamide 454 (2R)—N-((1S,2R)-1-(1,3- 566.4 0.020 0.027 36 1660.3 1.8 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)tetrahydro-2-furancarboxamide 455 (2R)—N-((1S,2R)-1-(1,3- 557.4 0.049 0.231 211 2012.6 5.5 benzodioxol-5-ylmethyl)- 3-(((4S)-2-(2,2- dimethylpropyl)-4,7-dihydro-5H-spiro[1- benzothiophene-6,1′- cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 456 (2S)—N-((1S,2R)-1-(1,3- 557.30.359 0.723 74 97 0.9 3.1 benzodioxol-5-ylmethyl)- 3-(((4S)-2-(2,2-dimethylpropyl)-4,7- dihydro-5H-spiro[1- benzothiophene-6,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxypropanamide 457N-((1S,2R)-1-(1,3- 580.2 0.792 0.905 44 90 0.1 2.4benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2,2- dimethyl-3- oxobutanamide 458 N-((1S,2R)-1-(3,5-583.4 0.017 0.012 25.5 188.5 0.1 0.9 difluorobenzyl)-2-hydroxy-3-(((4S)-8-(1H-imidazol-1- yl)-6-(2-methylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 459 (2R)—N-((1S,2R)-1-(3,5- 614.3 0.004 0.046 399 3990.4 10.2 difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2- methylpropyl)-8-(1,3-thiazol-2-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 460 N-((1S,2R)-1-(3,5- 600.30.001 0.028 775 775 0.8 3.9 difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2-methylpropyl)-8-(1,3- thiazol-2-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 461(2R)—N-((1S,2R)-1-(3,5- 597.4 0.026 0.028 28 126 0 2.2difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1H-imidazol-1-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 462 N-((1S,2R)-3-(((4′S)-6′-490.3 0.432 0.649 107 68 8.5 16.9 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- ((3R)-tetrahydro-3- furanylmethyl)propyl)-2-(methyloxy)acetamide 463 N-((1S,2R)-1-(3,5- 614.3 0.003 0.048 682 6621.1 7.2 difluorobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-8-(1,3-thiazol-2-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 464N-((1S,2R)-3-(((4S)-8- 610.2 0.004 0.091 463 364 1.5 11.5 bromo-6-(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-((3,5- difluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 465 N-((1S,2R)-1-(3,5- 568.4 0.019 0.032 18.5 51.50.1 1 difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)acetamide 466N-((1S,2R)-3-(((4′S)-6′- 526.7 0.004 0.008 296 165 1.2 8.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-3- oxobutanamide 467 N-((1S,2R)-3-(((4′S)-6′- 553.7 0.0630.209 399 292 0.4 7.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2- hydroxypropyl)-2,2-dimethyl-3- oxobutanamide 468 N-((1S,2R)-3-(((4′S)-6′- 528.4 0.097 0.108736 662 0.5 9.6 (2,2-dimethylpropyl)-7′- methyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 469 N-((1S,2R)-3-(((4′S)-6′- 460.2 0.137 0.162 6035 16.4 27 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1-((3S)-tetrahydro-3- furanylmethyl)propyl)acetamide 470 N-((1S,2R)-1-((3-0.004 0.014 579 560 1.1 5.8 cyanophenyl)methyl)-3- (((4′S)-6′-(2,2-dimethylpropyl)-3,3- difluoro-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-(methyloxy)acetamide 471 (2R)—N-((1S,2R)-1-((3- 0.004 0.012 569 536 1.110.3 cyanophenyl)methyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-3,3-difluoro-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- (methyloxy)propanamide 472(2R)—N-((1S,2R)-1-((3- 0.005 0.015 736 775 0.8 7.1cyanophenyl)methyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-3,3-difluoro-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)tetrahydro- 2-furancarboxamide 473N-((1S,2R)-1-((3- 0.009 0.063 590 775 0.6 2.4 cyanophenyl)methyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3,3- difluoro-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-3-fluoro-2- pyridinecarboxamide 474N-((1S,2R)-3-(((4′S)-6′- 527.3 0.013 0.022 172 174 2 6.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- ((2-(methyloxy)-4-pyridinyl)methyl)propyl)-2- (methyloxy)acetamide 475 N-((1S,2R)-1-(3,5-596.4 0.018 0.008 26 128.5 0.05 1.75 difluorobenzyl)-3-(((4S)-6-(2,2-dimethylpropyl)-8- (1H-imidazol-1-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 476(2R)—N-((1S,2R)-1-(3,5- 597.4 0.028 0.005 329 408 0.6 12.3difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1H-imidazol-5-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 477 N-((1S,2R)-3-(((4′S)-6′-534.2 0.012 0.104 118 337 0.3 3.2 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2,2-difluoropropanamide 478 N-((1S,2R)-1-(4- 565.4 0.056 0.068 24 157 0.12.2 fluorobenzyl)-2-hydroxy-3- (((4S)-8-(1H-imidazol-1-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 479 N-((1S,2R)-1-((3,5- 560.3 0.0110.017 167 329 1.8 6.4 difluorophenyl)methyl)-3- (((4S)-6-(2,2-dimethylpropyl)-8- (methylamino)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- (methyloxy)acetamide480 N-((1S,2R)-1-(3,5- 583.2 0.023 0.006 272 405 0.5 10.1difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1H-imidazol-5-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 481 N-((1S,2R)-1-(3,5- 585.2 0.0040.123 155 177 0.2 7.9 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (1,3-thiazol-5-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)acetamide 482 (2R)—N-((1S,2R)-1-(4- 579.4 0.150 0.422 27194 0.1 3.6 fluorobenzyl)-2-hydroxy-3- (((4S)-8-(1H-imidazol-1-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 483 (2S)—N-((1S,2R)-1-(1,3- 542.40.018 0.049 83 308 0.1 3.8 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-fluoropropanamide 484 (2R)—N-((1S,2R)-1-(1,3- 542.4 0.029 0.056 42 1140.2 2.3 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-fluoropropanamide 485 N-((1S,2R)-1-(1,3- 558.4 0.120 0.378 43 106 0.11.7 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-7′-fluoro- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 486 N-((1S,2R)-1-(3,5- 613.4 0.004 0.033 408 380 0.212.8 difluorobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-8-(1,3-thiazol-5-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 487 N-((1S,2R)-1-((3,5-625.3 0.015 0.118 394 387 1.6 21.4 difluorophenyl)methyl)-3-(((4S)-6-(2,2- dimethylpropyl)-8-(2- fluorophenyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- (methyloxy)acetamide 488 N-((1S,2R)-1-(3,5- 607.40.009 0.010 31 82 0.1 1.6 difluorobenzyl)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 489N-((1S,2R)-1-(3,5- 607.4 0.007 0.020 399 775 0.4 3.9difluorobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-8-(3- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 490 N-((1S,2R)-1-(3,5- 600.3 0.0030.029 344 249 0.2 7.5 difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2-methylpropyl)-8-(1,3- thiazol-5-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 491(2R)—N-((1S,2R)-1-(3,5- 614.3 0.004 0.036 345 285 0.2 6.2difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2- methylpropyl)-8-(1,3-thiazol-5-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 421 N-((1S,2R)-3-(((4′S)-6′-569.2 0.134 0.054 211 151 1.3 3.6 (2,2-dimethylpropyl)-8′-(4-morpholinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 492 N-((1S,2R)-3-(((4′R)-8′- 539.4 5.043 0.46294 190 0.4 8.2 cyano-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 493 N-((1S,2R)-3-(((4′S)-8′- 539.4 0.044 0.471 95221 0.6 11.6 cyano-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 494 N-((1S,2R)-1-(3,5- 598.4 0.020 0.072 30 63 0.21.2 difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 495 (2R)—N-((1S,2R)-1-(3,5- 612.4 0.020 0.080 41 62 0.12 difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 496 N-((1S,2R)-3-(((4′S)-6′-(2- 524.8 0.024 0.102 89139 4.7 27 cyano-2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- (methyloxy)acetamide 497 N-((1S,2R)-3-(((4′S)-8′-553.4 0.077 0.100 157 172 3.3 2.6 (cyclobutylamino)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 498 N-((1S,2R)-1-(1,3- 529.1 0.268 0.377 119 2060.5 0.7 benzodioxol-5-ylmethyl)- 3-(((4S)-6-((2R)-2- fluoropropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 499 (2S)—N-((1S,2R)-1-(1,3- 543.11.364 0.473 156 213 0.3 0.7 benzodioxol-5-ylmethyl)- 3-(((4S)-6-((2R)-2-fluoropropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxypropanamide 500N-((1S,2R)-3-(((4R)-6′- 550.4 1.741 1.948 50 286 0.1 1.7(2,2-dimethylpropyl)-8′- (1H-imidazol-1-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)acetamide 501 (2R)—N-((1S,2R)-3-(((4′R)-594.4 5.304 >10.000000 86 175 0.1 2.8 6′-(2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 502 N-((1S,2R)-3-(((4′R)-6′- 580.41.995 1.852 54 158 0.1 0.8 (2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 503 N-((1S,2R)-1-(1,3- 552.4 0.0210.017 23 130 0.2 3.3 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-oxetanecarboxamide 504 N-((1S,2R)-3-(((4′S)-6′- 580.4 0.014 0.028 16 870.1 2.3 (2,2-dimethylpropyl)-8′- (1H-imidazol-1-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 505N-((1S,2R)-3-(((4S)-6- 578.4 0.019 0.006 51.5 153 0.1 1.9(2,2-dimethylpropyl)-8- (1H-imidazol-1-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3- fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 506 N-((1S,2R)-3-(((4′S)-6′- 550.4 0.021 0.020 14 610.1 2.2 (2,2-dimethylpropyl)-8′- (1H-imidazol-1-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)acetamide 507 (2R)—N-((1S,2R)-3-(((4′S)-594.4 0.022 0.057 14 95 0.1 1.9 6′-(2,2-dimethylpropyl)-8′-(1H-imidazol-1-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 508 N-((1S,2R)-1-(3,5- 598.4 0.0240.005 17 43 0.1 1.2 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (1H-imidazol-5-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 509 N-((1S,2R)-1-(3,5- 598.4 0.4870.077 74 70 0.1 2.3 difluorobenzyl)-3-(((4′R)-6′-(2,2-dimethylpropyl)-8′- (1H-imidazol-5-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 510 N-((1S,2R)-1-(3,5- 585.4 0.0080.017 380 358 1.1 10.3 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (1,3-thiazol-4-yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)acetamide 511 (2R)—N-((1S,2R)-3-(((4′S)- 557.2 0.007 0.011382 203 2.4 14.5 6′-(2-cyano-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5- difluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)propanamide 512 N-((1S,2R)-1-((3- 503.2 0.028 0.061 614 8295.7 0.5 fluorophenyl)methyl)-3- (((4S)-6-((2S)-2- fluoropropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- (methyloxy)acetamide 513 N-((1S,2R)-1-(4- 565.4 0.0880.013 143 82 0.2 2.5 fluorobenzyl)-2-hydroxy-3- (((4S)-8-(1H-imidazol-5-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 514 N-((1S,2R)-3-(((4S)-8- 577.3,0.003 0.128 682 560 1.5 6 bromo-6-(2-methylpropyl)- 579.3 3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-((3-fluorophenyl)methyl)-2- hydroxypropyl)-2- (methyloxy)acetamide 515(2R)—N-((1S,2R)-3-(((4S)- 591.3, 0.003 0.125 775 399 1.3 9.48-bromo-6-(2- 593.3 methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-((3- fluorophenyl)methyl)-2-hydroxypropyl)-2- (methyloxy)propanamide 516 (2R)—N-((1S,2R)-1-(1,3- 5520.018 0.020 31 94 0.1 3.3 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-oxetanecarboxamide 517 N-((1S,2R)-1-(1,3- 522.2 0.178 0.202 32 51 0.57.8 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′- yl)amino)propyl)acetamide 518N-((1S,2R)-1-(1,3- 552.3 0.131 0.340 26 82 0.3 2.7benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 519(2R)—N-((1S,2R)-1-(1,3- 566.3 0.255 0.810 33 71 0.3 7.4benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2,2,2-trifluoroethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide440 (2R)—N-((1S,2R)-3-(((4′S)- 526 0.016 0.035 209 242 0.7 8.26′-(2,2-dimethylpropyl)- 3′4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- oxetanecarboxamide 520 N-((1S,2R)-1-(3- 565.4 0.0180.009 32 144 0.1 0.9 fluorobenzyl)-2-hydroxy-3- (((4S)-8-(1H-imidazol-1-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 521 (2R)—N-((1S,2R)-1-(3- 579.40.019 0.015 27 142 0.1 1.9 fluorobenzyl)-2-hydroxy-3-(((4S)-8-(1H-imidazol-1- yl)-6-(2-methylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxypropanamide 522 (2R)—N-((1S,2R)-3-(((4S)- 592.4 0.044 0.013 43141 0.1 3.1 6-(2,2-dimethylpropyl)-8- (1H-imidazol-1-yl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 523N-((1S,2R)-1-(1,3- 570.4 0.019 0.033 37 94 0.1 5.4benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2,2- dimethoxyacetamide 524 (2R)—N-((1S,2R)-1-(3- 596.30.008 0.065 492 472 0.5 7.5 fluorobenzyl)-2-hydroxy-3-(((4S)-6-(2-methylpropyl)- 8-(1,3-thiazol-4-yl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxypropanamide 525 (2S)—N-((1S,2R)-1-(1,3- 552.3 0.021 0.019 32 1010.2 3.1 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-oxetanecarboxamide 526 N-((1S,2R)-1-(3- 582.3 0.006 0.053 351 503 0.67.3 fluorobenzyl)-2-hydroxy-3- (((4S)-6-(2-methylpropyl)-8-(1,3-thiazol-4-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 527 (2R)—N-((1S,2R)-3-(((4′S)-605.2 0.222 1.953 33 108 0.1 0.6 6′-(2,2-dimethylpropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 528 N-((1S,2R)-1-(3,5- 609.2 0.0100.023 19 72 0.1 1.3 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (4-pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 529 N-((1S,2R)-3-(((4′S)-6′- 580.40.023 0.012 37 40 0.1 0.7 (2,2-dimethylpropyl)-8′-(1H-imidazol-4-yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 530 N-((1S,2R)-1-(3- 594.4 0.0150.010 fluorobenzyl)-3-(((4S)-6- (2-fluoro-2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 531N-((1S,2R)-3-(((4′S)-6′- 591.4 0.013 0.029 40 159 0.2 1.3(2,2-dimethylpropyl)-8′-(4- pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 532 N-((1S,2R)-3-(((4′S)-6′- 561.40.012 0.022 40 91 0.2 2.6 (2,2-dimethylpropyl)-8′-(4- pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)acetamide 533 (2R)—N-((1S,2R)-3-(((4′S)-605.4 0.013 0.044 29 163 0 1.4 6′-(2,2-dimethylpropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 534 (2R)—N-((1S,2R)-3-(((4′S)-511.2 0.023 0.014 178 113 0.5 3.6 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (4-pyridinylmethyl)propyl)- 2-(methyloxy)propanamide 535 N-((1S,2R)-3-(((4S)-6- 589.4 0.009 0.006 4979 0.1 2.5 (2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 536N-((1S,2R)-3-(((4S)-6-(2- 610.3 0.019 0.011 27 27chloro-2-methylpropyl)-8- (4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3- fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 537 (2R)—N-((1S,2R)-3-(((4′S)- 541.3 0.020 0.028 194125 1 3 6′-(2,2-dimethylpropyl)- 3′4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- ((2-(methyloxy)-4-pyridinyl)methyl)propyl)-2- (methyloxy)propanamide 538 N-((1S,2R)-1-(4-594.2 0.047 0.043 fluorobenzyl)-3-(((4S)-6- (2-fluoro-2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 539(2R)—N-((1S,2R)-1-(1,3- 572 4.767 0.147 61 161 0.1 6.5benzodioxol-5-ylmethyl)- 3-(((3′S,4′R)-6′-(2,2-dimethylpropyl)-3′-fluoro- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 540 N-((1S,2R)-3-(((4′S)-6′- 470 0.014 0.074 264 3471.2 2.3 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)formamide 541 N-((1S,2R)-3-(((4′S)-6′- 573.4 0.020 0.05531 192 0.1 2.1 (2,2-dimethylpropyl)-8′-(4- pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2- (methyloxy)acetamide542 N-((1S,2R)-1-benzyl-3- 543.4 0.024 0.103 36 193 0.2 27(((4′S)-6′-(2,2- dimethylpropyl)-8′-(4- pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)acetamide 543 (2R)—N-((1S,2R)-1-benzyl- 587.4 0.037 0.25541 242 0.1 2.6 3-(((4′S)-6′-(2,2- dimethylpropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- methoxypropanamide 544N-((1S,2R)-3-(((4S)-8- 559.2, 0.005 0.937 399 662 1.8 7bromo-6-(2-methylpropyl)- 561.2 3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 545 (2R)—N-((1S,2R)-3-(((4S)- 573.3, 0.007 1.485775 775 1.1 8.2 8-bromo-6-(2- 575.3 methylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1-(phenylmethyl)propyl)-2- (methyloxy)propanamide 546N-((1S,2R)-1-benzyl-2- 547.4 0.025 0.033 75 267 0.1 3.8hydroxy-3-(((4S)-8-(1H- imidazol-1-yl)-6-(2- methylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 547 (2R)—N-((1S,2R)-1-benzyl- 561.4 0.042 0.073 53 2600.1 4.4 2-hydroxy-3-(((4S)-8-(1H- imidazol-1-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 548 (2S)—N-((1S,2R)-1-(1,3- 552.30.074 0.623 57 184 0.3 3.7 benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)tetrahydro- 2-furancarboxamide 549N-((1S,2R)-3-(((4′S)-6′- 591.4 0.071 0.296 38 122 0.1 2(2,2-dimethylpropyl)-8′-(4- pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 550 N-((1S,2R)-3-(((4S)-6- 554 0.0420.474 338 315 0.2 0.5 chloro-8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3- fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 551 (2R)—N-((1S,2R)-1-(1,3- 552.3 0.044 0.367 33 1120.1 5.7 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′- yl)amino)propyl)tetrahydro-2-furancarboxamide 552 (2S)—N-((1S,2R)-1-(1,3- 528.3 0.049 0.369 73 2530.2 2.3 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- fluoropropanamide 553N-((1S,2R)-3-(((4S)-6- 543.2 0.146 47 86 chloro-8-(1H-imidazol-1-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 441(2S)—N-((1S,2R)-3-(((4′S)- 526 0.012 0.012 416 124 1.1 276′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- oxetanecarboxamide 554 (2R)—N-((1S,2R)-1-(1,3- 5720.057 1.025 63 173 0.2 6.5 benzodioxol-5-ylmethyl)-3-(((3′R,4′R)-6′-(2,2- dimethylpropyl)-3′-fluoro- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 555 (2R)—N-((1S,2R)-1-(1,3- 543.13.425 >10.000000 269 543 0.4 0.9 benzodioxol-5-ylmethyl)-3-(((4S)-6-((2S)-2- fluoropropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxypropanamide556 (2R)—N-((1S,2R)-1-(1,3- 543.2 0.718 0.446 211 353 0.3 1benzodioxol-5-ylmethyl)- 3-(((4S)-6-((2R)-2- fluoropropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 557 N-((1S,2R)-1-(1,3- 529.23.787 >10.000000 193 344 0.3 0.5 benzodioxol-5-ylmethyl)-3-(((4S)-6-((2S)-2- fluoropropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 558N-((1S,2R)-1-(1,3- 529.1 0.250 0.336 167 362 benzodioxol-5-ylmethyl)-3-(((4S)-6-((2R)-2- fluoropropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 559N-((1S,2R)-1-((3- 503.2 0.027 0.038 706 829 7.1 1.1fluorophenyl)methyl)-3- (((4S)-6-((2R)-2- fluoropropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- (methyloxy)acetamide 560 N-((1S,2R)-3-(((4S)-6- 572.30.049 0.058 209 829 0.2 0.4 chloro-8-(4-pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3,5-difluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 561(2R)—N-((1S,2R)-3-(((4S)- 586.3 0.092 0.262 113 426 0.1 0.46-chloro-8-(4-pyridinyl)- 3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3,5- difluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 562 N-((1S,2R)-3-(((4S)-6- 589.40.027 0.021 24 60 0.1 3.6 (2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 563 N-((1S,2R)-1-(3-645.4 12.041 >10.000000 40 40 0.1 0.4 fluorobenzyl)-2-hydroxy-3-(((4S)-8-(1H-imidazol-1- yl)-6-((1R)-1-(1H-imidazol-1-yl)-2,2-dimethylpropyl)- 3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 564(2R)—N-((1S,2R)-1-(3- 608.4 0.032 0.029 fluorobenzyl)-3-(((4S)-6-(2-fluoro-2-methylpropyl)- 8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxypropanamide565 N-((1S,2R)-3-(((4′S)-6′- 542 0.049 0.267 921 829 0.6 23.8(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2-((1- methylethyl)oxy)acetamide 566(2R)—N-((1S,2R)-3-(((4′S)- 542 0.026 0.165 392 590 0.3 136′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- (methyloxy)butanamide 567 (2R)—N-((1S,2R)-1-(3- 606.30.039 0.009 67 120 0.1 2.2 fluorobenzyl)-2-hydroxy-3-(((4S)-6-(2-hydroxy-2- methylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxypropanamide 568 N-((1S,2R)-1-(3,5- 624.3 0.025 0.019 214 304 0.29.3 difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(3-pyridinylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 569 N-((1S,2R)-3-(((4′S)-6′- 550.2 0.165 0.992 238 4230.7 27 (1,1-difluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 570 N-((1S,2R)-3-(((4′S)-6′- 520.2 0.136 0.405 101162 0.8 7.1 (1,1-difluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)acetamide 571N-((1S,2R)-1-(3,5- 624.3 0.053 0.003 142 193 0.1 2.3difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(4-pyridinylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 572 (2S)—N-((1S,2R)-3-(((4′S)- 542 0.102 0.094 290 5690.2 8.1 6′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2- (methyloxy)butanamide 573 N-((1S,2R)-1-(1,3- 576.10.280 0.627 40 187 0.1 3.2 benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(1,1-difluoro- 2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 574 N-((1S,2R)-1-(1,3- 546.1 0.2200.606 46 146 0.2 3.5 benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(1,1-difluoro- 2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)acetamide 575 N-((1S,2R)-1-(1,3- 538.2 0.010 0.016 33 1940.1 1.5 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 576 N-((1S,2R)-1-(1,3- 538.2 0.328 0.249 31 209 0.1 2.7benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-((1S)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 577 (2R)—N-((1S,2R)-1-(4- 608.2 0.115 0.057fluorobenzyl)-3-(((4S)-6- (2-fluoro-2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxypropanamide 578(2R)—N-((1S,2R)-1-(1,3- 552.2 0.018 0.019 36 185 0.1 2benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 579 N-((1S,2R)-1-(3,5- 612.2 0.014 0.005difluorobenzyl)-3-(((4S)-6- (2-fluoro-2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 580(2R)—N-((1S,2R)-1-(1,3- 552.2 0.357 0.776 42 186 0.1 4.4benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-((1S)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 581 N-((1S,2R)-3-(((4S)-6- 561.3 0.081 0.075 91 124chloro-8-(1H-imidazol-1- yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3,5- difluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 582 N-((1S,2R)-3-(((4S)-6- 542.20.024 0.057 97 829 0.1 0.4 chloro-8-(4-pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3,5-difluorobenzyl)-2- hydroxypropyl)acetamide 583 (2R)—N-((1S,2R)-1-(3,5-623.3 0.015 0.030 14 80 0 1.2 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (4-pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 584 N-((1S,2R)-1-(3,5- 579.3 0.0110.013 18 50 0.1 14.5 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (4-pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)acetamide 585 (2R)—N-((1S,2R)-3-(((4S)- 603.3 0.016 0.01265.5 120 0.05 0.75 6-(2,2-dimethylpropyl)-8- (4-pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 586N-((1S,2R)-1-(3,5- 594.3 0.009 0.006 31 65 0.1 1.3difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2- methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 587 (2R)—N-((1S,2R)-1-(3,5- 608.30.012 0.006 29 73 0 2.1 difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2-methylpropyl)-8-(4- pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxypropanamide 588N-((1S,2R)-1-(3- 583.3 0.027 0.006 25 74 0.1 0.6fluorobenzyl)-3-(((4S)-6- (2-fluoro-2-methylpropyl)-8-(1H-imidazol-1-yl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 589 N-((1S,2R)-1-(3-563.3 0.257 0.105 27 217 0.2 0.2 fluorobenzyl)-2-hydroxy-3-(((4S)-8-(1H-imidazol-1- yl)-6-(2-methyl-1-propen- 1-yl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 423 N-((1S,2R)-1-(3- 595.3 0.579 0.063 35 132 0.1 0.3fluorobenzyl)-2-hydroxy-3- (((4S)-8-(1H-imidazol-1- yl)-6-(2-methoxy-2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 590 (2R)—N-((1S,2R)-1-(3,5- 626.20.024 0.007 60 105 0 0.6 difluorobenzyl)-3-(((4S)-6-(2-fluoro-2-methylpropyl)- 8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxypropanamide591 N-((1S,2R)-3-(((4′S)-6′- 0.010 0.018 356 375 0.6 10.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)-2,2- bis(methyloxy)acetamide 592 N-((1S,2R)-3-(((4S)-6-559.3 0.010 0.004 14 73 0 1.7 (2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)acetamide 593 N-((1S,2R)-1-(3- 595.31.591 0.312 14 29 0.1 1 fluorobenzyl)-2-hydroxy-3-(((4S)-6-((1S)-1-hydroxy- 2,2-dimethylpropyl)-8-(1H- imidazol-1-yl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 594 N-((1S,2R)-3-(((4S)-6- 513.2 0.158 0.077 44 61 00.3 chloro-8-(1H-imidazol-1- yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)acetamide 595 N-((1S,2R)-3-(((4S)-6- 524.2 0.077 0.051 147736 0.1 0.5 chloro-8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)acetamide 596 N-((1S,2R)-1-(3,5- 612.3 0.041 0.009 26 390.1 2.9 difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(1-methyl-1H-imidazol-2- yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 597 N-((1S,2R)-1-(3,5- 612.3 0.034 0.011 22 35 0 2.8difluorobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-8′-(1-methyl-1H-imidazol-5- yl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 598 N-((1S,2R)-1-((3,5- 593.2 0.023 0.260 103 102 6.927 difluorophenyl)methyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-8′-(phenylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)acetamide 599N-((1S,2R)-1-((3,5- 623.2 0.018 0.395 120 125 6.4 27difluorophenyl)methyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-8′-(phenylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-(methyloxy)acetamide 600 (2R)—N-((1S,2R)-1-(1,3- 528.3 0.030 0.035benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- fluoropropanamide 601 (2S)—N-((1S,2R)-1-(1,3-528.3 0.044 0.062 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- fluoropropanamide 602N-((1S,2R)-3-(((4′S)-6′- 561.2 0.023 0.018 124 78 0.16 0.4(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(4-pyridinyl)benzyl)-2- hydroxypropyl)acetamide 603N-((1S,2R)-1-benzyl-2- 558.3 0.010 0.010 76 172 0 2.7hydroxy-3-(((4S)-6-(2- methylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 604 (2R)—N-((1S,2R)-1-benzyl- 572.3 0.018 0.013 89 2150 2.7 2-hydroxy-3-(((4S)-6-(2- methylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxypropanamide 605 N-((1S,2R)-1-(4- 576.3 0.014 0.016 73 71 0 2.3fluorobenzyl)-2-hydroxy-3- (((4S)-6-(2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 606 (2R)—N-((1S,2R)-1-(4- 590.30.041 0.026 51 85 0 2 fluorobenzyl)-2-hydroxy-3-(((4S)-6-(2-methylpropyl)- 8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxypropanamide 607N-((1S,2R)-1-(3- 576.3 0.010 0.007 65 72 0 1.7fluorobenzyl)-2-hydroxy-3- (((4S)-6-(2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 608 (2S)—N-((1S,2R)-3-(((4′S)-524.1 0.008 0.016 232 183 4.5 12.2 6′-(2,2-difluoropropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3- fluorophenyl)methyl)-2- hydroxypropyl)-2-fluoropropanamide 609 (2R)—N-((1S,2R)-1-(3- 590.3 0.008 0.005 64 137 0.12 fluorobenzyl)-2-hydroxy-3- (((4S)-6-(2-methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 610 N-((1S,2R)-3-(((4′S)-6′-575.4 0.199 10.000 102 213 27 27 (2,2-dimethylpropyl)-8′-(phenylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-((4- fluorophenyl)methyl)-2-hydroxypropyl)acetamide 611 N-((1S,2R)-3-(((4S)-6- 485.4 0.103 0.116 644775 18.4 1.2 ((2S)-2-fluoropropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1- (phenylmethyl)propyl)-2-(methyloxy)acetamide 612 N-((1S,2R)-3-(((4′S)-6′- 605.3 0.210 10.000 176245 27 27 (2,2-dimethylpropyl)-8′- (phenylamino)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((4- fluorophenyl)methyl)-2- hydroxypropyl)-2-(methyloxy)acetamide 613 N-((1S,2R)-3-(((4′S)-6′- 591.1 0.020 0.011 228142 0.16 0.3 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(4-pyridinyl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 614N-((1S,2R)-3-(((4′S)-6′- 561.2 0.012 0.008 244 107 0.16 0.4(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(4-pyridinyl)benzyl)-2- hydroxypropyl)acetamide 615N-((1S,2R)-3-(((4′S)-6′- 532.2 0.060 0.007 59 32 0.16 0.16(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1H-imidazol-1-yl)benzyl)propyl)acetamide 616 N-((1S,2R)-3-(((4′S)-6′- 543.2 0.0170.010 228 96 0.16 0.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(4- pyridinyl)benzyl)propyl)acetamide 617N-((1S,2R)-3-(((4′S)-6′- 549.2 0.004 0.006 71 70 0.16 0.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)acetamide 618 N-((1S,2R)-3-(((4S)-6- 542.2 0.031 0.038413 344 0.16 0.3 (2,2-dimethylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1-(3- (4-pyridinyl)benzyl)propyl)acetamide 619 N-((1S,2R)-1-(3- 583.2 0.012 0.00635 85 0 1.5 cyanobenzyl)-2-hydroxy- 3-(((4S)-6-(2- methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 620 (2R)—N-((1S,2R)-1-(3- only0.010 0.005 48 105 0 1.9 cyanobenzyl)-2-hydroxy- NMR 3-(((4S)-6-(2-methylpropyl)-8-(4- pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxypropanamide 621N-((1S,2R)-3-(((4′S)-6′- 567.2 0.001 0.010 45 64 0.16 0.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)acetamide 433N-((1S,2R)-3-(((4S)-6- 560.2 0.021 0.038 492 590 1.1 0.2(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-(3-fluoro-5-(4- pyridinyl)benzyl)-2- hydroxypropyl)acetamide622 (2R)—N-((1S,2R)-1-(3,5- 611.3 0.026 0.007 32 161 0 6.6difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1-methyl-1H- imidazol-5-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 623 N-((1S,2R)-3-(((4′S)-6′-543.2 0.008 0.006 829 601 0.16 1.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(3- pyridinyl)benzyl)propyl)acetamide 624N-((1S,2R)-1-((7-bromo- 592 0.200 0.081 48 150 0.16 1.21,3-benzodioxol-5- yl)methyl)-3-(((4′S)-6′-(2- fluoro-2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)acetamide 625 N-((1S,2R)-3-(((4S)-6- 560.20.042 0.057 389 330 0.16 0.2 (2,2-dimethylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(4-fluoro-3-(4-pyridinyl)benzyl)-2- hydroxypropyl)acetamide 626 (2R)—N-((1S,2R)-1-(1,3-566.7 0.133 0.108 153 260 0.5 14.4 benzodioxol-5-ylmethyl)-3-(((5′S)-3′-(2,2- dimethylpropyl)-8′-oxo- 5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′- quinolin]-5′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 627 N-((1S,2R)-3-(((4′S)-6′- 538.2 0.007 0.047 829166 2.1 26.1 (1,1-difluoro-2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-((3,5- difluorophenyl)methyl)-2- hydroxypropyl)acetamide628 N-((1S,2R)-2-hydroxy-3- 559.3 0.045 0.007 94 239 0.1 1.9(((4S)-6-(2-methylpropyl)- 8-(4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(4- pyridinylmethyl)propyl)-2-methoxyacetamide 629 N-((1S,2R)-3-(((4′S)-8′- 652.3 0.009 0.121 171 2091.2 27 (1,3-benzodioxol-5-yl)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3,5- difluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 630 N-((1S,2R)-1-(3,5- 597.3 0.021 0.003 37 220 0 4difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1-methyl-1H- imidazol-2-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 631 N-((1S,2R)-1-(3,5- 597.3 0.0190.004 36 209 0.1 3.9 difluorobenzyl)-2-hydroxy- 3-(((4S)-8-(1-methyl-1H-imidazol-5-yl)-6-(2- methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 632(2R)—N-((1S,2R)-3-(((4S)- 593.2 0.065 0.015 57 166 0 3.16-(2,2-dimethylpropyl)-8- (4-pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1- (1,3-thiazol-5-ylmethyl)propyl)-2- methoxypropanamide 633 N-((1S,2R)-3-(((4S)-6- 579.20.021 0.011 53 153 0.1 3 (2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1-(1,3-thiazol-5- ylmethyl)propyl)-2- methoxyacetamide 634(2R)—N-((1S,2R)-1-benzyl- 574.3 0.126 0.014 50 340 0.1 4.52-hydroxy-3-(((4S)-8-(1- methyl-1H-imidazol-5-yl)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 635 N-((1S,2R)-1-benzyl-2- 560.30.074 0.010 44 420 0 4.1 hydroxy-3-(((4S)-8-(1-methyl-1H-imidazol-5-yl)- 6-(2-methylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 636N-((1S,2R)-1-(3- 596.3 0.008 0.005 32 90 0.1 3 cyanobenzyl)-3-(((4S)-6-(2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 637N-((1S,2R)-1-(3- 566.3 0.010 0.004 34 105 0.1 2.8cyanobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)acetamide 638 (2R)—N-((1S,2R)-1-(3- 610.3 0.017 0.006 3292 0 3 cyanobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 639 N-((1S,2R)-3-(((4S)-8-(2- 624.30.005 0.025 706 399 1.2 1.8 chloro-4-pyridinyl)-6-(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-(3- fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 435N-((1S,2R)-3-(((4S)-6- 566.2 0.006 0.039 125 197 1.4 0.3(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)acetamide 640 N-((1S,2R)-3-(((4S)-6- 566.2 0.006 0.053 59113 0.7 0.3 (2,2-dimethylpropyl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)acetamide 641N-((1S,2R)-3-(((4S)-6- 548.2 0.006 0.029 102 165 0.7 0.3(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2- yl)benzyl)propyl)acetamide 642N-((1S,2R)-3-(((4′S)-6′- 573.2 0.034 0.010 182 103 0.16 0.16(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(4-pyridinyl)benzyl)propyl)-2- methoxyacetamide 643N-((1S,2R)-3-(((4′S)-6′- 567.2 0.002 0.012 68 56 0.1 0.7(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)acetamide 644N-((1S,2R)-3-(((4′S)-6′- 597.2 0.002 0.007 53 68 0.1 0.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 432N-((1S,2R)-3-(((4S)-6- 549.2 0.006 0.332 280 323 1.5 3.1(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-(4-fluoro-3-(2- furanyl)benzyl)-2- hydroxypropyl)acetamide645 N-((1S,2R)-3-(((4′S)-6′- 587.1 0.441 0.406 451 62 0.1 0.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1-((7-(4-pyridinyl)-1,3- benzodioxol-5- yl)methyl)propyl)acetamide 646N-((1S,2R)-3-(((4S)-6- 549.2 0.004 0.104 326 344 2 1.6(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-1-(3-fluoro-5-(2- furanyl)benzyl)-2- hydroxypropyl)acetamide647 2-(difluoromethoxy)-N- 550.2 0.008 0.039 303 269 0.4 2.7((1S,2R)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)acetamide 648 N-((1S,2R)-3-(((4S)-6-560.2 0.008 0.045 551 560 0.1 0.4 (2,2-dimethylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(4-fluoro-3-(3-pyridinyl)benzyl)-2- hydroxypropyl)acetamide 649 N-((1S,2R)-3-(((4S)-6-560.2 0.007 0.030 706 482 0.3 0.5 (2,2-dimethylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluoro-5-(3-pyridinyl)benzyl)-2- hydroxypropyl)acetamide 650N-((1S,2R)-3-(((4′S)-6′- 597.2 0.008 0.015 14 62 0.16 0.6(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 651(2R)—N-((1S,2R)-1-(3,4- 542.2 0.008 0.012 171 147 1.6 10.8dihydroxybenzyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 652 (2R)—N-((1S,2R)-1-(3,5- 626.30.028 0.020 26 50 0.16 2 difluorobenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′- (1-methyl-1H-imidazol-5- yl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 653 (2R)—N-((1S,2R)-2- 509.2 6.73510.000 178 114 0.6 5.8 hydroxy-1-(4- pyridinylmethyl)-3-(((4′S)-6′-(trifluoromethyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide654 N-((1S,2R)-3-(((4S)-6- 619.3 0.006 0.034 399 477 1 9.9(2,2-dimethylpropyl)-8-(2- methoxy-4-pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 655N-((1S,2R)-3-(((4′S)-6′- 528.2 0.013 0.043 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-2- ethoxyacetamide 656N-((1S,2R)-1-(1,3- 560.2 0.051 0.774 131 180 0.1 5.3benzodioxol-5-ylmethyl)- 3-(((4′S)-8′-chloro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 657 (2R)—N-((1S,2R)-1-(1,3- 574.20.030 0.524 96 178 0.16 5.3 benzodioxol-5-ylmethyl)-3-(((4′S)-8′-chloro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 658 N-((1S,2R)-3-(((4′S)-6′- 549.20.006 0.010 130 120 0.1 0.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-5- yl)benzyl)propyl)acetamide659 N-((1S,2R)-3-(((4S)-6- 531.2 0.076 0.024 706 413 0 0.2(2,2-dimethylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3- (1H-imidazol-1- yl)benzyl)propyl)acetamide 660N-((1S,2R)-3-(((4′S)-6′- 528.2 0.003 0.018 829 775 0.2 1.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2- ethoxyacetamide 661 N-((1S,2R)-3-(((4′S)-6′- 538.20.003 0.011 57 97 0.2 1.2 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl- 4-fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 662 N-((1S,2R)-3-(((4′S)-6′- 597.2 0.004 0.025 78 74 00.2 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-5-yl)benzyl)-2- hydroxypropyl)acetamide 663N-((1S,2R)-3-(((4S)-6- 502.3 0.013 0.021 163 133 1.7 10.5(2,2-dimethylpropyl)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4- yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 664 N-((1S,2R)-1-(1,3- 526.2 0.1180.192 193 276 0.03 2.3 benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 665 (2R)—N-((1S,2R)-1-(1,3-568.1 0.927 0.249 61 126 0.2 4 benzodioxol-5-ylmethyl)-2-hydroxy-3-(((3′S,5′S)-3′- (1-methylethyl)-2′,3′,5′,6′-tetrahydrospiro[cyclobutane- 1,7′-furo[2,3- b]pyrano[3,2-e]pyridin]-5′-yl)amino)propyl)-2- methoxypropanamide 666 (2R)—N-((1S,2R)-1-(1,3- 540.20.124 0.175 140 228 0.03 2.4 benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxypropanamide 667 N-((1S,2R)-3-(((4′S)-8′-552.2 0.005 0.054 399 682 0.6 6.3 chloro-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3,5- difluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 668 N-((1S,2R)-3-(((4S)-6- 607.3 0.004 0.018 118 1970.1 2.9 (2,2-dimethylpropyl)-8-(3- fluoro-4-pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 669N-((1S,2R)-1-(1,3- 603.2 0.034 0.087 45 77 0.03 0.3benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 670 (2R)—N-((1S,2R)-1-(1,3-617.3 0.060 0.294 40 100 0.03 0.8 benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-8′-(4- pyridinyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxypropanamide 671 N-((1S,2R)-3-(((4′S)-6′-567.2 0.005 0.012 99 48 0.1 0.4 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-5-yl)benzyl)-2-hydroxypropyl)acetamide 672 N-((1S,2R)-3-(((4′S)-6′- 567.2 0.004 0.005358 134 0.4 2.7 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-4-yl)benzyl)-2- hydroxypropyl)acetamide 673N-((1S,2R)-1-(3,5- 564.3 0.009 0.005 46 118 0.03 0.8difluorobenzyl)-2-hydroxy- 3-(((4S)-6-(2- methylpropyl)-8-(4-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)acetamide 674 (2R)—N-((1S,2R)-1-(1,3- 542.3 0.033 0.03726 128 0.1 10.5 benzodioxol-5-ylmethyl)- 3-(((4S)-6-(2,2-dimethylpropyl)-2,2- dimethyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4-yl)amino)-2- hydroxypropyl)-2- methoxypropanamide 675(2R)—N-((1S,2R)-1-(3,4- 534.2 0.009 0.013 543 411 2 21.8difluorobenzyl)-3-(((4S)-6- (2,2-dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4- yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 676 N-((1S,2R)-1-(3,4- 520.2 0.0100.011 463 411 2 2.9 difluorobenzyl)-3-(((4S)-6-(2,2-dimethylpropyl)-2,2- dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide436 N-((1S,2R)-3-(((4′S)-6′- 567.2 0.005 0.024 135 78 0.2 2.2(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-4-yl)benzyl)-2- hydroxypropyl)acetamide 677N-((1S,2R)-3-(((4′S)-6′- 549.2 0.015 0.028 57 52 0.1 1(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (4-(1,3-thiazol-2-yl)benzyl)propyl)acetamide 678 N-((1S,2R)-1-(3,5- 607.2 0.018 0.010 2379 0.1 1.3 difluorobenzyl)-3-(((4′S)- 6′-((1S)-2,2-dimethylcyclopropyl)-8′-(4- pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 439 N-((1S,2R)-3-(((4S)-8-(2- 632.3 0.020 0.005 601 5151.3 4.1 (dimethylamino)-4- pyridinyl)-6-(2,2- dimethylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 679N-((1S,2R)-1-(1,3- 498.3 0.019 0.012 24 138 0.2 5.7benzodioxol-5-ylmethyl)- 3-(((4S)-6-(2,2- dimethylpropyl)-2,2-dimethyl-3,4-dihydro-2H- pyrano[2,3-b]pyridin-4- yl)amino)-2-hydroxypropyl)acetamide 680 (2R)—N-((1S,2R)-1-(1,3- 569.3 0.140 0.025220 317 0.5 14 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-8′-(methylamino)-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide681 N-((1S,2R)-1-(1,3- 555.3 0.064 0.014 197 392 0.8 9.2benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-8′- (methylamino)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 682N-((1S,2R)-1-(3,5- 595.3 0.009 0.011 34 113 0 1.1difluorobenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 426 N-((1S,2R)-3-(((4′S)-6′-550.5 0.031 0.011 22 14 0.03 0.1 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3- (1H-imidazol-1-yl)benzyl)- 2-hydroxypropyl)acetamide 683 N-((1S,2R)-3-(((4′S)-6′- 597.2 0.009 0.031102 61 0.2 2.3 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-4-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 684N-((1S,2R)-3-(((4′S)-6′- 597.2 0.005 0.012 56 114 0.1 0.2(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-5-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 685(2R)—N-((1S,2R)-3-(((4′S)- 659 0.013 0.012 662 283 0.2 3.16′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-(3- methylbenzyl)-2- morpholinecarboxamide 686(2R)—N-((1S,2R)-3-(((4′S)- 566.2 0.003 0.052 921 399 0.2 6.18′-chloro-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3,5- difluorobenzyl)-2-hydroxypropyl)-2- methoxypropanamide 687 (2R)—N-((1S,2R)-1-(3,5- 609.30.008 0.016 27 91 0.03 0.2 difluorobenzyl)-2-hydroxy- 3-(((4′S)-6′-(2-methylpropyl)-8′-(4- pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide688 (2R)—N-((1S,2R)-1-(3,5- 532.2 0.009 0.036 921 399 0.2 3difluorobenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxypropanamide 689 N-((1S,2R)-1-(3,5- 550.20.038 0.027 18.5 44.5 0.03 0.2 difluorobenzyl)-3-(((4S)-6-ethynyl-8-(1H-imidazol-1- yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 690(2R)—N-((1S,2R)-3-(((4′S)- 611.2 0.011 0.040 40 53 0.1 0.56′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 691(2S)—N-((1S,2R)-3-(((4′S)- 659 0.078 0.104 543 426 0.2 36′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-(3- methylbenzyl)-2- morpholinecarboxamide 692(2R)—N-((1S,2R)-3-(((4′S)- 659 0.013 0.024 706 590 0.2 5.16′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-(2- methylbenzyl)-2- morpholinecarboxamide 693N-((1S,2R)-3-(((4′S)-6′- 549.2 0.043 0.060 110 63 0.2 2.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (4-(1,3-thiazol-4-yl)benzyl)propyl)acetamide 694 N-((1S,2R)-3-(((4′S)-6′- 549.2 0.0740.071 82 66 0.2 0.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (4-(1,3-thiazol-5- yl)benzyl)propyl)acetamide695 N-((1S,2R)-1-(3-fluoro-5- 583.2 0.004 0.011 77 64 0.1 0.5(1,3-thiazol-2-yl)benzyl)-2- hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 696N-((1S,2R)-3-(((4S)-6- 529.2 40.000 0.778 32 44 2.9 27(2,2-dimethylpropyl)-3,4- dihydrospiro[pyrano[2,3-c]pyridine-2,3′-pyrrolidin]- 4-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 697 (2S)—N-((1S,2R)-3-(((4′S)- 6590.087 0.143 775 399 0.2 2.7 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-(2- methylbenzyl)-2-morpholinecarboxamide 698 N-((1S,2R)-3-(((4′S)-6′- 562.2 0.026 0.009 5833 0.03 0.1 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1H-imidazol-1-yl)benzyl)propyl)-2- methoxyacetamide 699 N-((1S,2R)-3-(((4′S)-6′- 579.20.004 0.007 54 66 0.1 0.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 700 N-((1S,2R)-3-(((4′S)-6′- 579.2 0.007 0.010 221 1150.1 2.7 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-4-yl)benzyl)propyl)-2- methoxyacetamide 701 N-((1R,2S)-3-(((4S)-6- 5780.008 0.033 137 160 0.2 0.7 (2,2-dimethylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2- yl)benzyl)propyl)-2- methoxyacetamide 702N-((1S,2R)-3-(((4S)-6- 499.2 36.359 0.454 14 26 1.8 13.5(2,2-dimethylpropyl)-3,4- dihydrospiro[pyrano[2,3-c]pyridine-2,3′-pyrrolidin]- 4-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)acetamide 703 N-((1S,2R)-1-(3,5- 607.2 1.226 0.302 32 1180.2 2.1 difluorobenzyl)-3-(((4′S)- 6′-((1S)-2,2-dimethylcyclopropyl)-8′-(4- pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 704 (2R)—N-((1S,2R)-1-(3,5- 612.3 0.030 0.024 20 440.03 27 difluorobenzyl)-2-hydroxy- 3-(((4′S)-8′-(1-methyl-1H-imidazol-2-yl)-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide705 N-((1S,2R)-3-(((4S)-6- 537.2 0.032 0.013 51 36 0 0.6cyclopropyl-8-(1H- imidazol-1-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3,5- difluorobenzyl)-2-hydroxypropyl)acetamide 706 N-((1S,2R)-3-(((4S)-6- 567.3 0.062 0.020 4133 0.1 0.3 cyclopropyl-8-(1H- imidazol-1-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)-1-(3,5- difluorobenzyl)-2-hydroxypropyl)-2- methoxyacetamide 707 (2R)—N-((1S,2R)-3-(((4S)- 581.30.114 0.028 14 39 0.03 0.6 6-cyclopropyl-8-(1H- imidazol-1-yl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3,5-difluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 428N-((1S,2R)-3-(((4′S)-6′- 550.2 0.061 0.013 225 124 0.3 1.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1H-imidazol-2-yl)benzyl)- 2- hydroxypropyl)acetamide 429N-((1S,2R)-3-(((4′S)-6′- 532.2 3.590 0.600 88 37 1.3 0.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1H-imidazol-2-yl)benzyl)propyl)acetamide 708 (2S)—N-((1S,2R)-3-(((4′S)- 659 0.1540.257 310 278 0.2 6.8 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-(4- methylbenzyl)-2-morpholinecarboxamide 709 (2R)—N-((1S,2R)-3-(((4′S)- 659 0.028 0.038 614375 0.3 3.7 6′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-(4- methylbenzyl)-2- morpholinecarboxamide 710(2R)—N-((1S,2R)-1-(3,5- 612.3 0.026 0.018 16 39 0.1 2.8difluorobenzyl)-2-hydroxy- 3-(((4′S)-8′-(1-methyl-1H-imidazol-5-yl)-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide426 N-((1S,2R)-1-(3,5- 607.2 0.005 0.005 21 66 0.1 1.3difluorobenzyl)-3-(((4′S)- 6′-((1R)-2,2- dimethylcyclopropyl)-8′-(4-pyridinyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 711(2S)-4-benzyl-N-((1S,2R)- 645 0.040 0.124 706 399 0.3 8.23-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- morpholinecarboxamide 712 N-((1S,2R)-3-(((4′S)-6′-579.2 0.005 0.009 74 75 0.03 0.2 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-5- yl)benzyl)propyl)-2-methoxyacetamide 713 N-((1S,2R)-3-(((4′S)-6′- 508.2 0.003 0.015 75 580.1 1.2 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2- hydroxypropyl)acetamide 714 N-((1S,2R)-1-(3,5- 598.30.016 0.017 20 43 0.03 2.2 difluorobenzyl)-2-hydroxy-3-(((4′S)-8′-(1-methyl-1H- imidazol-2-yl)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 715 N-((1S,2R)-1-(3,5- 598.30.020 0.016 19 34 0.03 1.8 difluorobenzyl)-2-hydroxy-3-(((4′S)-8′-(1-methyl-1H- imidazol-5-yl)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 716 N-((1S,2R)-3-(((4′S)-6′-626.2 0.032 0.025 123 190 0.4 1.5 (2,2-dimethylpropyl)-8′-(methylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 717(2R)-4-benzyl-N-((1S,2R)- 645 0.013 0.011 775 298 0.2 3.63-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-2- morpholinecarboxamide 718 N-((1S,2R)-3-(((4′S)-6′-(2-601.2 0.051 0.062 113 140 0.3 0.5 fluoro-2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 719 (2R)—N-((1S,2R)-1-(3- 566.2 0.0240.130 515 775 0.4 2.4 chloro-5-fluorobenzyl)-3- (((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 720 N-((1S,2R)-1-(1,3- 540.2 0.057 0.134benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- ethoxyacetamide 721 (2R)—N-((1S,2R)-3-(((4′S)-615.2 0.049 0.118 111 152 0.3 0.5 6′-(2-fluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 722 N-((1S,2R)-3- 611.3 0.005 0.02050 111 0.03 0.6 (((1s,3R,4′S)-6′-(2,2- dimethylpropyl)-3-methyl- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 723 N-((1S,2R)-3- 613.3 0.006 0.00586 199 0.6 11.2 (((1s,3S,4′S)-6′-(2,2- dimethylpropyl)-3- hydroxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 724 N-((1S,2R)-3-(((4′S)-6′-(2- 601.30.006 0.009 45 38 0.2 0.9 fluoro-2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 725 N-((1S,2R)-1-(3,5- 529.2 0.0590.178 difluorobenzyl)-3-(((7S)-9- (2,2-dimethylpropyl)-5,5-dimethyl-2,3,6,7- tetrahydro-5H- [1,4]oxazino[2,3,4-ij]quinolin-7-yl)amino)-2- hydroxypropyl)acetamide 726N-((1S,2R)-1-(1,3- 510 0.044 0.048 34 173 0.03 1.4benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)propanamide 727 N-((1S,2R)-1-(4-fluoro-3- 583.2 0.0110.023 45 74 0.03 0.5 (1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 728N-((1S,2R)-3-(((4′S)-6′- 555.2 0.030 0.108 ethyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 729 N-((1S,2R)-3-(((4′S)-6′- 611.20.048 0.291 371 399 0.4 3.9 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3- (5-methyl-1,3-thiazol-2- yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 730 N-((1S,2R)-3-(((4′S)-6′- 597.20.039 0.027 57 74 0.03 0.7 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-4- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 731 N-((1S,2R)-3-(((4′S)-6′- 579.20.029 0.026 68 63 0.03 0.9 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (4-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 732 N-((1S,2R)-1-(3-fluoro-5- 597.2 0.018 0.083 551 3990.2 2.5 (5-methyl-1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 733N-((1S,2R)-1-(3-fluoro-5- 597.2 0.008 0.021 249 399 0.03 4.5(4-methyl-1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 734(2S)—N-((1S,2R)-3-(((4′S)- 666 0.012 0.014 543 335 0.1 2.46′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-((4- methyl-1,3-thiazol-2- yl)methyl)-2-morpholinecarboxamide 735 (2R)—N-((1S,2R)-3-(((4′S)- 593.2 0.049 0.06078 80 0.03 1 6′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (4-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxypropanamide 736 (2R)—N-((1S,2R)-3-(((4′S)-593.2 0.008 0.009 35 51 0.03 0.5 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxypropanamide 737 N-((1S,2R)-3-(((4′S)-6′- 520.2 0.005 0.008 43 450.03 2 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 738 (2R)—N-((1S,2R)-3-(((4′S)- 611.20.008 0.010 50 59 0.03 0.6 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 739 (2R)—N-((1S,2R)-3-(((4′S)- 5690.064 0.008 266 239 0.8 6.7 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-methyl- 2-morpholinecarboxamide 740N-((1S,2R)-3-(((4′S)-6′- 594.2 0.051 0.006 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1-methyl-1H-imidazol-2- yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 741 (2R)—N-((1S,2R)-1-(1,3- 558.20.352 0.329 25 76 0.03 5 benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2-fluoro-2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxypropanamide 742 (2R)—N-((1S,2R)-3-(((4′S)- 615.2 0.084 0.045 39.542 0.7 0.95 6′-(2-fluoro-2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 743 N-((1S,2R)-3-(((4′S)-6′-(2-601.2 0.016 0.037 22 31 0.03 0.6 fluoro-2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 744 (2S)—N-((1S,2R)-3-(((4′S)- 5690.372 0.075 333 266 0.9 11.2 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-methyl- 2-morpholinecarboxamide 745N-((1S,2R)-3-(((6S)-4- 553.1 5.727 0.229 179 177 0.5 3.1bromo-8,8-dimethyl-7,8- dihydro-6H- [1,3]dioxolo[4,5-h]chromen-6-yl)amino)-1- (4-fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 746 N-((1S,2R)-3-(((6S)-4- 571.1 0.275 0.185 150 1440.2 3.8 bromo-8,8-dimethyl-7,8- dihydro-6H- [1,3]dioxolo[4,5-h]chromen-6-yl)amino)-1- (3,5-difluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 747 N-((1S,2R)-3-(((6S)-8,8- 553.2 0.209 0.243 125 2170.2 9.1 dimethyl-4-(2- methylpropyl)-7,8-dihydro- 6H-[1,3]dioxolo[4,5-h]chromen-6-yl)amino)-1- (4-fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 748 N-((1S,2R)-1-(3,5- 571.2 0.013 0.126 190 179 0.18.2 difluorobenzyl)-3-(((6S)- 8,8-dimethyl-4-(2-methylpropyl)-7,8-dihydro- 6H-[1,3]dioxolo[4,5- h]chromen-6-yl)amino)-2-hydroxypropyl)-2- methoxyacetamide 749 N-((1S,2R)-3-(((4′S)-6′- 567.20.046 0.074 59 51 0.3 1.6 cyclopropyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 750N-((1S,2R)-3- 627.2 0.012 0.014 190 426 0.5 3.1 (((1s,3S,4′S)-6′-(2,2-dimethylpropyl)-3- methoxy-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 751(2R)—N-((1S,2R)-3- 641.2 0.016 0.027 192 497 0.3 1.7(((1s,3S,4′S)-6′-(2,2- dimethylpropyl)-3- methoxy-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 752 (2R)—N-((1S,2R)-3-(((4′S)-631.2 0.009 0.067 166 137 0.1 1.3 8′-chloro-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 573 N-((1S,2R)-3-(((4′S)-8′- 617.20.006 0.067 158 123 0.2 1.4 chloro-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 754 N-((1S,2R)-1-(1,3- 556.2 0.0370.054 29 86 0.1 3.5 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2,2- dimethoxyacetamide755 (2R)—N-((1S,2R)-3-(((4′S)- 666 0.012 0.007 522 191 0.3 3.36′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-((2- methyl-1,3-thiazol-4- yl)methyl)-2-morpholinecarboxamide 756 N-((1S,2R)-1-(3- 506.2 0.005 0.009 53 49 0 1.4ethynylbenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 757 N-((1S,2R)-2-hydroxy-3-565.2 0.007 0.018 60 60 0.25 0.45 (((4′S)-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3- thiazol-2- yl)benzyl)propyl)-2- methoxyacetamide758 N-((1S,2R)-3-(((4′S)-6′- 593.2 0.006 0.014 347 311 0.1 4.4(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1-(3-(4-methyl-1,3-thiazol-2- yl)benzyl)propyl)-2- methoxyacetamide 759N-((1S,2R)-3-(((4′S)-6′- 593.2 0.021 0.071 436 399 0.3 1.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1-(3-(5-methyl-1,3-thiazol-2- yl)benzyl)propyl)-2- methoxyacetamide 760(2R)—N-((1S,2R)-3-(((4′S)- 615.2 0.031 0.100 26 31 0.3 0.86′-(2-fluoro-2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 761(2R)—N-((1S,2R)-1-(3- 597.2 1.616 0.375 85 74 0.1 0.7fluoro-5-(1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide762 (2S)—N-((1S,2R)-3-(((4′S)- 666 0.037 0.037 297 522 0.3 2.66′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-((2- methyl-1,3-thiazol-4- yl)methyl)-2-morpholinecarboxamide 763 N-((1S,2R)-1-(3- 528.2 2.502 1.302 399 399 2 2fluorobenzyl)-2-hydroxy-3- (((3′S,5′S)-3′-(1- methylethyl)-2′,3′,5′,6′-tetrahydrospiro[cyclobutane- 1,7′-furo[2,3- b]pyrano[3,2-e]pyridin]-5′-yl)amino)propyl)-2- methoxyacetamide 764 N-((1S,2R)-3-((6′-(2,2- 605.10.011 0.018 41 33 0.3 0.7 difluoropropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 765 (2R)—N-((1S,2R)-3-((6′- 619.20.021 0.054 35 39 0.2 0.7 (2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 766 N-((1S,2R)-3-(((4′S)-6′- 550.20.055 0.272 70 64 0.2 1.4 ethynyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 767N-((1S,2R)-1-(1,3- 601.3 0.198 0.251 157 150 0.1 3.6benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4S)-6-(2- methylpropyl)-8-(2-pyridinyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxyacetamide 768 (2R)—N-((1S,2R)-1-(4- 597.20.022 0.105 39 70 0.1 0.4 fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3- (((4′S)-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxypropanamide 769 (2S)—N-((1S,2R)-3-(((4′S)-652 0.010 0.013 706 333 0.4 5.2 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-(1,3- thiazol-2-ylmethyl)-2-morpholinecarboxamide 770 (2R)—N-((1S,2R)-1-(3- 596.2 0.010 0.052 145201 0.3 0.5 fluoro-5-(1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4S)-6-(2-methylpropyl)- 3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxypropanamide 771N-((1S,2R)-1-(3-fluoro-5- 582.2 0.005 0.040 150 201 0.7 0.5(1,3-thiazol-2-yl)benzyl)-2- hydroxy-3-(((4S)-6-(2- methylpropyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)propyl)-2-methoxyacetamide 772 N-((1S,2R)-1-(1,3- 554.2 0.021 0.042 28 112 0.2 1.1benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- ethoxyacetamide 773 N-((1S,2R)-3-(((4′S)-6′- 595.20.003 0.006 62 67 0.3 0.3 ((1R)-2,2- dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 774 (2R)—N-((1S,2R)-3-(((4′S)- 6520.017 0.006 111 57 0.2 5.3 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-(1,3- thiazol-4-ylmethyl)-2-morpholinecarboxamide 775 N-((1S,2R)-3-(((4′S)-6′- 576.3 0.064 0.006 1614 0.1 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1-(3-(1-methyl-1H-imidazol- 2-yl)benzyl)propyl)-2- methoxyacetamide 776(2R)—N-((1S,2R)-2- 579.2 0.014 0.027 58 61 0.2 0.7hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-(1,3- thiazol-2-yl)benzyl)propyl)-2- methoxypropanamide 777 (2R)—N-((1S,2R)-1-(3- 520.20.006 0.013 29 38 0.1 2.1 ethynylbenzyl)-2-hydroxy- 3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide778 N-((1S,2R)-1-(1,3- 628.2 0.048 0.050 62 141 0.1 8.5benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2-(1,1- dioxidotetrahydro-3- thiophenyl)acetamide 779N-((1S,2R)-1-(1,3- 614.4 0.057 0.075 36 66 0.1 3.9benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)tetrahydro- 3-thiophenecarboxamide 1,1-dioxide 780N-((1S,2R)-1-(3-ethynyl-4- 524.2 0.010 0.032 61 74 0.1 1.4fluorobenzyl)-2-hydroxy-3- (((4′S)-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 781 (2R)—N-((1S,2R)-3-(((4′S)-594.2 0.071 0.206 104 82 0.4 27 6′-(2,2-dimethylpropyl)-8′-(2-pyridinyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-2-hydroxy-1- (1,3-thiazol-5-ylmethyl)propyl)-2- methoxypropanamide 782 N-((1S,2R)-3-(((4′S)-6′-597.2 0.015 0.036 94 130 0.3 0.4 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 783 N-((1S,2R)-3-(((4S)-6- 578.20.031 0.029 73 107 0.3 0.3 cyclopropyl-8-(4- pyridinyl)-3,4-dihydrospiro[chromene- 2,1′-cyclobutan]-4- yl)amino)-1-(3,5-difluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 784(2R)—N-((1S,2R)-3-(((4′S)- 564.1 0.158 0.864 51 64 0.03 16′-ethynyl-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxypropanamide 785 N-((1S,2R)-3-(((4′S)-6′- 562.20.018 0.019 43 37 0.1 0.4 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-oxazol-2- yl)benzyl)propyl)-2-methoxyacetamide 434 N-((1S,2R)-2-hydroxy-3- 565.2 0.075 0.273 80 60 0.21.3 (((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-(1,3- thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 786 (2S)—N-((1S,2R)-3-(((4′S)- 6520.047 0.029 169 129 0.3 7.9 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluorobenzyl)-2- hydroxypropyl)-4-(1,3- thiazol-4-ylmethyl)-2-morpholinecarboxamide 787 N-((1S,2R)-1-(3-fluoro-4- 583.2 0.110 0.451 5879 0.2 0.8 (1,3-thiazol-2-yl)benzyl)-2- hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 788(2S)—N-((1S,2R)-3-(((4′S)- 652 0.016 0.013 267 157 0 0.66′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- fluorobenzyl)-2-hydroxypropyl)-4-(1,3- thiazol-5-ylmethyl)-2- morpholinecarboxamide 789(2S)—N-((1S,2R)-3-(((4′S)- 593.2 0.007 0.020 42 15 0.1 0.66′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxypropanamide 790 (2S)—N-((1S,2R)-3-(((4′S)-605.2 0.008 0.007 64 44 0.1 0.6 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro- 2-furancarboxamide 791N-((1S,2R)-3-(((4′S)-6′- 593.2 0.009 0.012 43 33 0.1 0.6(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-3- methoxypropanamide 792 (2R)—N-((1S,2R)-3-(((4′S)-605.2 0.008 0.010 46 35 0.1 0.6 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro- 2-furancarboxamide 793N-((1S,2R)-3-(((4′S)-6′- 565.2 0.030 0.067 99 60 0.1 0.4(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)ethanethioamide 794 (2R)—N-((1S,2R)-3-(((4′S)- 515.20.005 0.009 205 132 0.5 9.8 6′-((1R)-2,2- dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (1,3-thiazol-5- ylmethyl)propyl)-2-methoxypropanamide 795 (2R)—N-((1R,2S)-2- 591.2 0.286 0.206 127 64 0.20.6 hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3- thiazol-2- yl)benzyl)propyl)tetrahydro-2-furancarboxamide 796 (2S)—N-((1R,2S)-2- 591.2 40.000 0.663 126 58 0.20.6 hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3- thiazol-2- yl)benzyl)propyl)tetrahydro-2-furancarboxamide 797 N-((1S,2R)-3-(((4′S)-6′- 0.008 0.017 256 199 1.44.1 (2,2-difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- fluorobenzyl)-2-hydroxypropyl)-2,2- dimethoxyacetamide 798 N-((1S,2R)-1-(3- 0.006 0.005468 423 0.5 4.7 cyanobenzyl)-3-(((4′S)-6′- (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2,2- dimethoxyacetamide 799 N-((1S,2R)-1-(3-chloro-5-0.008 0.019 663 236.5 0.5 4.95 fluorobenzyl)-3-(((4′S)-6′-(2,2-difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 800 N-((1S,2R)-1-(3- 562.1 0.004 0.013 921 459 0.2 1.4bromobenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 801 (2R)—N-((1S,2R)-1-(3- 574.10.016 0.118 399 644 0.3 3.8 bromobenzyl)-2-hydroxy- 3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide802 N-((1S,2R)-2-hydroxy-3- 520.2 0.005 0.032 60.5 191 0.1 2.15(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-(1- propyn-1-yl)benzyl)propyl)-2- methoxyacetamide 803 (2R)—N-((1S,2R)-2- 534.2 0.0220.132 hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1- propyn-1- yl)benzyl)propyl)-2- methoxypropanamide804 N-((1S,2R)-2-hydroxy-3- 548.2 0.009 0.030 61 43 0.2 2.5(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-(1,3- oxazol-2-yl)benzyl)propyl)-2- methoxyacetamide 805 (2R)—N-((1S,2R)-1-(3- 547.20.003 0.070 chloro-5-fluorobenzyl)-2- hydroxy-3-(((4S)-6-(2-methylpropyl)-3,4- dihydrospiro[chromene- 2,1′-cyclobutan]-4-yl)amino)propyl)-2- methoxypropanamide 806 N-((1S,2R)-1-(3-fluoro-5-563.1 0.669 4.145 61 92 0.2 0.6 (1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4S)-6-(1- propyn-1-yl)-3,4- dihydrospiro[chromene-2,1′-cyclobutan]-4- yl)amino)propyl)-2- methoxyacetamide 807N-((1S,2R)-3-(((4′S)-6′- 579.2 0.019 0.054 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 808 (2R)—N-((1S,2R)-1-(1,3- 554 0.138 0.414 49 179 0.12.3 benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- ethoxypropanamide 809(2S)—N-((1S,2R)-1-(1,3- 554 0.269 0.513 33 117 0.2 6.7benzodioxol-5-ylmethyl)- 2-hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- ethoxypropanamide 810 N-((1R,2S)-3-(((4′S)-6′-577.2 4.485 1.340 274 271 0.1 0.5 cyclopentyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 811 N-((1S,2R)-2-hydroxy-3- 546.2 0.309 0.736 36 54 0.31 (((4′S)-6′-(1-propyn-1-yl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-(1,3- thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 812 N-((1S,2R)-1-(3- 543.2 0.2580.954 260 345 0.4 3 bromobenzyl)-2-hydroxy- 3-(((4′S)-6′-(1-propyn-1-yl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 813 N-((1S,2R)-3-(((4′S)-6′-(2-583.2 0.006 0.014 32 27 0.5 1.1 fluoro-2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 814 N-((1S,2R)-3-(((3S,4′S)-6′- 595.2 2.229 0.808 40112 0.5 8.1 (2,2-dimethylpropyl)- 3′,4,4′,5- tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′- yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 815 (2R)—N-((1R,2S)-1-(3- 583.2204 276 0.2 0.6 fluoro-5-(1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4′S)-6′-propyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide816 N-((1S,2R)-2-hydroxy-3- 595.2 0.008 0.024 46 44 0.3 0.7(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-(1,3- thiazol-2-yl)benzyl)propyl)-2,2- dimethoxyacetamide 817 N-((1S,2R)-3-(((4′S)-6′-609.2 0.009 0.013 33 41 0.2 1.4 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2,2-dimethoxyacetamide 818 N-((1S,2R)-3-(((4′S)-6′- 635.2 0.013 0.059 41 460.6 2.3 (2,2-difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2,2- dimethoxyacetamide 819N-((1S,2R)-1-benzyl-3- 0.013 0.074 736 543 0.2 2 (((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-4,4-dimethylpentanamide 820 (2R)—N-((1S,2R)-1-(3- 0.022 0.021 682 324 0.33.8 chloro-5-fluorobenzyl)-3- (((4′S)-6′-(2,2- difluoropropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 821 (2R)—N-((1R,2S)-3-(((4′S)- 62140.000 0.558 162 243 0.3 0.5 6′-bromo-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 822N-((1S,2R)-3-(((3R,4′S)- 595.2 4.417 2.762 54 101 0.2 4.96′-(2,2-dimethylpropyl)- 3′,4,4′,5- tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′- yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 823 N-((1S,2R)-3-(((3S,4′S)-6′-595.2 29.938 3.161 57 171 0.3 3.1 (2,2-dimethylpropyl)- 3′,4,4′,5-tetrahydrospiro[furan-3,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 824 N-((1S,2R)-3-(((3R,4′S)- 536.2 2.341 0.806 21 280.1 27 6′-(2,2-dimethylpropyl)- 3′,4,4′,5- tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′- yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 825 N-((1S,2R)-3-(((3S,4′S)-6′- 536.40.005 0.009 17 85 0.1 7.3 (2,2-dimethylpropyl)- 3′,4,4′,5-tetrahydrospiro[furan-3,2′- pyrano[2,3-b]pyridin]-4′- yl)amino)-1-(3-ethynylbenzyl)-2- hydroxypropyl)-2- methoxyacetamide 826N-((1S,2R)-3-(((4′S)-6′- 593.3 0.012 0.013 66 55 0.2 0.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-oxazol-2-yl)benzyl)propyl)-2,2- dimethoxyacetamide 827 N-((1S,2R)-3-(((3S,4′R)-595.2 0.006 0.007 97 197 0.5 2.1 6′-(2,2-dimethylpropyl)- 3′,4,4′,5-tetrahydrospiro[furan-3,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 828 N-((1S,2R)-1-(1,3- 524.2 0.012 0.014benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)propanamide 829 N-((1S,2R)-3-(((4′S)-6′- 0.007 0.016 40 230.2 2.3 (2,2-difluoropropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 830 N-((1S,2R)-3-(((4′S)-6′- 0.0070.023 28 35 0.1 1.3 (2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynylbenzyl)-2- hydroxypropyl)-2,2- dimethoxyacetamide 831(2R)—N-((1S,2R)-3-(((4′S)- 597.2 0.024 0.047 21 45 0.2 0.86′-(2-fluoro-2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxypropanamide 832 N-((1S,2R)-1-(3- 508.2 0.0070.038 ethenylbenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 833 N-((1R,2S)-1-(3-fluoro-5-569 40.000 2.278 219 189 0.3 0.9 (1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4′S)-6′- propyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 834(2R)—N-((1S,2R)-3-(((4′S)- 552.2 0.005 0.011 37 98 0 2.56′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 835(2R)—N-((1S,2R)-1-(3- 538.2 0.006 0.026 48 109 0 2.1ethynyl-5-fluorobenzyl)-2- hydroxy-3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxypropanamide 836 (2R)—N-((1S,2R)-3-(((4′S)-577.3 0.013 0.015 56 56 0.2 0.7 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-oxazol-2- yl)benzyl)propyl)-2-methoxypropanamide 837 N-((1S,2R)-3-(((4′S)-6′- 552 0.007 0.023 29 720.1 1.6 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-4-fluorobenzyl)-2- hydroxypropyl)-2- ethoxyacetamide 838N-((1S,2R)-1-(3- 574.2 0.010 0.028 34 54 0.1 2 ethynylbenzyl)-2-hydroxy-3-(((4′S)-6′-(3,3,3-trifluoro- 2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 839 N-((1S,2R)-3-(((4′S)-6′-662.2 0.258 0.477 62 57 0.1 0.4 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3,5-di-1,3- thiazol-2-ylbenzyl)-2- hydroxypropyl)-2-methoxyacetamide 840 N-((1S,2R)-3-(((4′S)-6′- 593.2 0.004 0.010(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- ethoxyacetamide 841 N-((1S,2R)-3-(((4′S)-6′- 573.10.009 0.018 706 292 0.4 3.3 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(2- pyridinyl)benzyl)propyl)-2-methoxyacetamide 842 N-((1S,2R)-3-(((4′S)-6′- 478.2 0.026 0.065 55 570.2 4.9 ethyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 843 N-((1S,2R)-1-(1,3- 548.2 0.0440.065 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-4- pentynamide 844 N-((1S,2R)-3-(((4′S)-6′- 0.005 0.00632 44 0.1 1.5 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2,2- dimethoxyacetamide 845 N-((1S,2R)-3-(((3R,4′S)-595.2 0.006 0.006 64 152 0.5 2.9 6′-(2,2-dimethylpropyl)- 3′,4,4′,5-tetrahydrospiro[furan-3,2′- pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2- yl)benzyl)propyl)-2-methoxyacetamide 846 N-((1S,2R)-3-(((3S,4′S)-6′- 595.2 0.007 0.006 82128 0.7 2.3 (2,2-dimethylpropyl)- 3′,4,4′,5- tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′- yl)amino)-2-hydroxy-1-(3- (1,3-thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 847 N-((1S,2R)-3-(((4′S)-6′- 626.20.044 0.010 102 201 0.4 0.8 (2,2-dimethylpropyl)-8′-(methylamino)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 848N-((1S,2R)-3-(((4′S)-6′- 522 0.005 0.019 36 60 0 0.9(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-4-fluorobenzyl)-2- hydroxypropyl)propanamide 849(2R)—N-((1S,2R)-3-(((4′S)- 534.4 0.005 0.008 18 43 0.05 3.26′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxypropanamide 850 N-((1S,2R)-3-(((4′S)-6′- 538.30.002 0.008 42 95 0.05 1.7 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl- 5-fluorobenzyl)-2- hydroxypropyl)-2-methoxyacetamide 851 N-((1S,2R)-1-(3-bromo-5- 659.1 0.013 0.057 71 590.2 0.7 (1,3-thiazol-2-yl)benzyl)-3- (((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 852 (2R)—N-((1S,2R)-3-(((4′S)- 621.1 0.246 0.094 106156 0.3 0.3 6′-bromo-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 853(2R)—N-((1S,2R)-1-(3- 583.3 0.043 0.075 93 101 0.4 0.7fluoro-5-(1,3-thiazol-2- yl)benzyl)-2-hydroxy-3-(((4′S)-6′-propyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxypropanamide854 N-((1S,2R)-3-(((4′S)-6′- 562.4 0.007 0.007 515 210 0.6 2.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1H-pyrazol-1-yl)benzyl)propyl)-2- methoxyacetamide 855 N-((1S,2R)-1-(4- 506.4 0.0620.174 ethynylbenzyl)-2-hydroxy- 3-(((4′S)-6′-(2- methylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 856 N-((1S,2R)-1-(3-ethynyl-5-524.3 0.002 0.009 63 78 0.15 1 fluorobenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)propyl)-2- methoxyacetamide 857N-((1S,2R)-3-(((4′S)-6′- 577 0.004 0.008 51 46 0.1 0.35 ((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 858 N-((1S,2R)-1-(3,5- 544 0.0050.147 90 88 1.1 diethynylbenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 859N-((1S,2R)-3-(((4′S)-6′- 522.2 0.004 0.027 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluorobenzyl)-2- hydroxypropyl)-4- pentynamide 860N-((1S,2R)-3-(((4′S)-6′- 581.2 0.004 0.015 62 69 0.2 0.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)propanamide 861N-((1S,2R)-3-(((4′S)-6′- 568 0.008 0.018 28 64 2.1(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-4-fluorobenzyl)-2- hydroxypropyl)-2,2- dimethoxyacetamide 862N-((1S,2R)-3-(((4′S)-6′- 611.2 0.004 0.009 43 64 0.3 0.65(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- ethoxyacetamide 8633-((2S,3R)-4-(((4′S)-6′-(2- 0.013 0.033 fluoro-2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-3-hydroxy-2- ((methoxyacetyl)amino)butyl)benzamide 8643-((2S,3R)-2- 0.040 0.117 ((dimethoxyacetyl)amino)-4-(((4′S)-6′-(2-fluoro-2- methylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-3- hydroxybutyl)benzamide 865N-((1S,2R)-1-(3-fluoro-5- 569.2 0.086 0.879 125 74 0.3 0.7(1,3-thiazol-2-yl)benzyl)-2- hydroxy-3-(((4′S)-6′- propyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2- methoxyacetamide 866 N-((1S,2R)-3-(((4′S)-6′-611.2 0.177 0.880 84 90 0.2 0.9 (2,2-dimethylpropyl)-4′- methyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 867 N-((1S,2R)-3-(((4′R)-6′- 611.21.213 1.145 66 119 0.7 (2,2-dimethylpropyl)-4′- methyl-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 868 N-((1S,2R)-3-(((3R,4′S)- 536.20.007 0.014 14 86 0.4 20.6 6′-(2,2-dimethylpropyl)- 3′,4,4′,5-tetrahydrospiro[furan-3,2′- pyrano[2,3-b]pyridin]-4′- yl)amino)-1-(3-ethynylbenzyl)-2- hydroxypropyl)-2- methoxyacetamide 869N-((1S,2R)-3-(((3S,4′S)-6′- 536.2 0.006 0.010 21 55 0.1 9.5(2,2-dimethylpropyl)- 3′,4,4′,5- tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′- yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 870 N-((1S,2R)-3-(((4′S)-6′- 534.20.004 0.011 0 1.6 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)-2- ethoxyacetamide 871 N-((1S,2R)-3-(((4′S)-6′- 0.0070.010 59 73 0.2 0.7 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2,2- dimethoxyacetamide 872 N-((1S,2R)-1-(3- 538.2 0.0070.009 382 278 5.7 acetylbenzyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methoxyacetamide 873 N-((1S,2R)-3-(((4′S)-6′- 504.2 0.003 0.007 35 29 00.8 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)propanamide 874 N-((1S,2R)-3-(((4′S)-6′- 593.2 0.008 0.02462 74 0.2 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)cyclopropanecarboxamide 875N-((1S,2R)-3-(((4′S)-6′- 607.2 0.006 0.020 65 81 0.2 0.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)cyclobutanecarboxamide 876N-((1S,2R)-3-(((4′S)-6′- 607.2 0.036 0.132 64 91 0.2 0.3(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-1-methylcyclopropanecarboxamide 877 (2R)—N-((1S,2R)-3-(((4′S)- 623.2 0.0050.012 46 64 0.2 0.7 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)tetrahydro- 2-furancarboxamide 878N-((1S,2R)-3-(((4′S)-6′- 585.2 0.004 0.022 72 65 0.2(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- fluoroacetamide 879(2S)—N-((1S,2R)-3-(((4′S)- 623.2 0.006 0.007 96 77 0.2 −0.66′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)tetrahydro-2-furancarboxamide 880 (2R)—N-((1S,2R)-3-(((4′S)- 605.2 20.965 0.063 71107 0.3 0.3 6′-(cyclopropylethynyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 881N-((1S,2R)-1-(1,3- 0.144 0.813 31 110 0.2 4 benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-methylpropanamide 882 N-((1S,2R)-1-(1,3- 6.249 2.575 40 103 0 0.5benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2,2- dimethylpropanamide 883 N-((1S,2R)-3-(((4′S)-6′-0.021 0.021 54 52 0.1 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methylpropanamide 884 (2R)—N-((1S,2R)-3-(((4′S)- 534.40.251 0.097 19 55 0.1 3.8 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-ethynylbenzyl)-2- hydroxypropyl)-2- methoxypropanamide 885N-((1S,2R)-3-(((4′S)-6′- 520.6 0.065 0.099 28 67 0.1 2.8(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4- ethynylbenzyl)-2-hydroxypropyl)-2- methoxyacetamide 886 N-((1S,2R)-3-(((4′S)-6′- 577.60.143 0.136 55 64 0.2 0.3 cyclopentyl-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxyacetamide 887 (2R)—N-((1S,2R)-1-(1,3- 568.30.102 0.052 37 136 0 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2- hydroxypropyl)-2-ethoxypropanamide 888 (2S)—N-((1S,2R)-1-(1,3- 568.2 0.213 1.555 29 140 03.4 benzodioxol-5-ylmethyl)- 3-(((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- ethoxypropanamide 889 N-((1S,2R)-3-(((4′S)-6′- 602.40.653 0.989 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-5-(1,3-thiazol-2-yl)benzyl)- 2-hydroxypropyl)-2- methoxyacetamide 890N-((1S,2R)-3-(((4′S)-6′- 563.2 0.011 0.414 39 45 0.1 0.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)propanamide 891 N-((1S,2R)-3-(((4′S)-6′- 534.2 0.0150.022 81 303 0 8.1 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1-propyn-1-yl)benzyl)propyl)-2- methoxyacetamide 892 N-((1S,2R)-1-(3,5- 654 0.0700.009 399 274 0.1 3.9 dibromobenzyl)-3-(((4′S)- 6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 893(2S)—N-((1S,2R)-3-(((4′S)- 607.2 0.013 0.012 36 71 0 1.16′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- ethoxypropanamide 894 (2R)—N-((1S,2R)-3-(((4′S)-607.2 0.016 0.018 38 88 0.1 0.9 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2- yl)benzyl)propyl)-2-ethoxypropanamide 895 (2R)—N-((1S,2R)-3-(((4′S)- 548.2 0.016 0.0176′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1-propyn-1-yl)benzyl)propyl)-2- methoxypropanamide 896 (2R)—N-((1S,2R)-3-(((4′S)-546.4 0.006 0.009 45 73 0 3.8 6′-(2,2-dimethylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynylbenzyl)-2- hydroxypropyl)tetrahydro- 2-furancarboxamide 897(2S)—N-((1S,2R)-3-(((4′S)- 546.4 0.005 0.007 19 55 0 3.66′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3- ethynylbenzyl)-2-hydroxypropyl)tetrahydro- 2-furancarboxamide 898(2R)—N-((1S,2R)-3-(((4′S)- 611.2 0.010 0.014 67 121 0.1 16′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(2-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 899(2R)—N-((1S,2R)-1-(5- 562.1 0.005 0.009 443 543 0.1 2.6chloro-2-fluorobenzyl)-3- (((4′S)-6′-(2,2- dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxypropyl)-2- methoxypropanamide 900 N-((1S,2R)-3-(((4′S)-6′- 597.20.010 0.018 63 55 27 27 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(2-fluoro-5- (1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2- methoxyacetamide 901 N-((1S,2R)-3-(((4′S)-6′- 577.30.010 0.032 74 62 27 24.8 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-oxazol-2- yl)benzyl)propyl)-2-ethoxyacetamide 902 (2R)—N-((1S,2R)-3-(((4′S)- 552.2 0.006 0.026 36 700.1 0.9 6′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(5-ethynyl-2-fluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 903N-((1S,2R)-3-(((4′S)-6′- 538.2 0.004 0.011 38 71 0.1 1.7(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(5-ethynyl-2-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 904N-((1S,2R)-3-(((4′S)-6′- 611.2 0.004 0.062 38 47 0.1 0.5(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- ethoxyacetamide 905(2R)—N-((1S,2R)-3-(((4′S)- 591 60 71 0.2 0.9 6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- methoxypropanamide 906 (2R)—N-((1S,2R)-3-(((4′S)-603 94 63 0.1 0.4 6′-((1R)-2,2- dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro- 2-furancarboxamide 907(2S)—N-((1S,2R)-3-(((4′S)- 603 77 78 0.1 0.5 6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro- 2-furancarboxamide 908N-((1S,2R)-3-(((4′S)-6′- 597.2 0.071 0.100 69 91 0.1 0.6(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(2-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxyacetamide 909(2R)—N-((1S,2R)-3-(((4′S)- 611.2 0.157 0.052 76 127 0.1 0.96′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(2-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)-2- methoxypropanamide 910(2S)—N-((1S,2R)-3-(((4′S)- 623.2 0.079 0.079 147 153 0.1 2.46′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(2-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2- hydroxypropyl)tetrahydro-2-furancarboxamide 911 N-((1S,2R)-3-(((4′S)-6′- 538.3 0.011 0.144 62 710.1 5.9 (2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-2-fluorobenzyl)-2- hydroxypropyl)-2- methoxyacetamide 912(2R)—N-((1S,2R)-3-(((4′S)- 552.3 0.013 1.187 35 60 0 6.36′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-2-fluorobenzyl)-2- hydroxypropyl)-2- methoxypropanamide 913(2S)—N-((1S,2R)-3-(((4′S)- 564.2 0.021 0.063 41 76 0 7.16′-(2,2-dimethylpropyl)- 3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-1-(3-ethynyl-2-fluorobenzyl)-2- hydroxypropyl)tetrahydro- 2-furancarboxamide 914N-((1S,2R)-3-(((4′S)-6′- 591.2 0.002 0.008 57 61 0.2 0.2 ((1R)-2,2-dimethylcyclopropyl)-3′,4′- dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]- 4′-yl)amino)-2-hydroxy-1- (3-(1,3-thiazol-2-yl)benzyl)propyl)-2- ethoxyacetamide 915 N-((1S,2R)-3-(((4′S)-6′- 566.41.959 0.562 921 590 0.6 6.8 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-((2S)-tetrahydro-2-furanyl)benzyl)propyl)-2- methoxyacetamide 916 N-((1S,2R)-3-(((4′S)-6′-566.3 9.500 2.254 399 644 0.4 8.1 (2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1- (3-((2R)-tetrahydro-2-furanyl)benzyl)propyl)-2- methoxyacetamide 917 N-((1S,2R)-1-(3-bromo-5-604.0, 0.014 methoxybenzyl)-3-(((4′S)- 606.0 6′-(2,2-dimethylpropyl)-3′,4′- dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2- hydroxypropyl)-2- methoxyacetamide 918N-((1S)-1-(3-fluoro-5-(1,3- 581.1 0.0164 >10.0 116 128 0.1 0.5thiazol-2-yl)benzyl)-3- (((4′S)-6′-(2-methylpropyl)- 3′,4′-dihydrospiro[cyclobutane- 1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-oxopropyl)- 2-methoxyacetamide

The present invention also provides methods for making compounds ofFormulas I-IV. In another embodiment of the invention, there is provideda method of making a compound of Formula I, the method comprising thestep of reacting a compound 20

wherein B, R³, R⁴ and R⁵ are as defined herein, with a compound havingthe structure

wherein R^(1a), R^(1b), R^(1c) and W are as defined herein and X is aleaving group, to make a compound of Formulas I or II.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula II, the method comprising the step ofreacting a compound 20-A

wherein R², R^(2a), R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, Z, m and n are asdefined hereinabove with respect to Formula II, with a compound havingthe structure

wherein R^(1a), R^(1b) and R^(1c) are as defined hereinabove and LG is aleaving group as defined herein, to prepare the compound of Formula II.In another embodiment, the LG may be selected from a halogen and an HOBtester.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula II, the method comprising the step ofreacting a compound 20-B

wherein R², R^(2a), R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, Z, m and n are asdefined hereinabove with respect to Formula II, with a compound havingthe structure

wherein R^(1a), R^(1b) and R^(1c) are as defined hereinabove and LG is aleaving group as defined herein, to prepare the compound of Formula II.In another embodiment, the LG may be selected from a halogen and an HOBtester.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula III, the method comprising the step ofreacting a compound 20-C

wherein R², R^(2a), R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, Z, m, n and p areas defined hereinabove with respect to Formula III, with a compoundhaving the structure

wherein R^(1a), R^(1b) and R^(1c) are as defined hereinabove and LG is aleaving group as defined herein, to prepare the compound of Formula III.In another embodiment, the LG may be selected from a halogen and an HOBtester.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula III, the method comprising the step ofreacting a compound 20-D

wherein R², R^(2a), R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, Z, m, n and p areas defined hereinabove with respect to Formula III, with a compoundhaving the structure

wherein R^(1a), R^(1b) and R^(1c) are as defined hereinabove and LG is aleaving group as defined herein, to prepare the compound of Formula III.In another embodiment, the LG may be selected from a halogen and an HOBtester.

In another embodiment of the invention, there is provided a method ofmaking a compound of Formula IV, the method comprising the step ofreacting a compound 30

wherein V, R², R³, R⁴ and R⁵ are as defined herein, with a compoundhaving the structure A-W—X, wherein A and W are as defined herein withrespect to Formula IV and X is a leaving group, to make a compound ofFormula IV.

Example 919

Step 1

A 5 L jacketed reactor was purged with nitrogen for 30 minutes and thencharged with 167 g (95 wt % assay) of tert-butyl(2S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-4-chloro-3-hydroxybutan-2-ylcarbamate1 (1.0 equiv, 485.7 mmol), DME (1000 mL) and pyridine (70 mL, 1.8 equiv,865.4 mmol). The contents of the reactor were cooled to 0° C. under ablanket of nitrogen and 100 mL of DME was added to help thin out thereaction mixture. A separate IL RBF was charged with PNPCF (150 g, 1.5equiv, 748 mmol.) and 400 mL of DME. The contents of the 1 L RBF weretransferred to the 5 L jacketed reactor via cannula over approximately15 minutes (addition is exothermic; Tmax=8° C. during addition). Oncethe transfer was complete, the reaction mixture was stirred for 30minutes at 0° C. and warmed to 25° C. over 10 minutes. The reaction wasjudged complete formation of 2 by HPLC (81279-3-2; <0.5%) after about 50minutes. Water (1500 mL) was added to the reaction mixture at such arate as to maintain the internal temperature below 50° C. (Tmax=35° C.).The contents of the reactor were warmed to 50° C. and monitored forbisnitrophenylcarbonate hydrolysis by HPLC. At 2 hours the hydrolysisreaction was judged complete (no detectable bisnitrophenyl carbonate)and the reaction mixture was cooled to 20° C. and stirred for 12 hours.A one mL sample of the reaction mixture was pulled, filtered through a0.45 micron filter and both solids and supernatant were analyzed by HPLC(no detectable 2; solids: no detectable bisnitrophenylcarbonate). Thecontents of the 5 L reactor were filtered. The mother liquors wererecycled through the reactor and passed through the wetcake tofacilitate product transfer from the reactor. The wet cake was washedwith 2×500 mL of 1:1 DME:water and 2×500 mL water. HPLC analysis of themother liquors showed no detectable presence of compound 2.

The product was dried on the filter by passing nitrogen through wetcakefor 2 hours and then dried in vacuo 36 h at 60° C. with a nitrogenbleed. Isolated the product in about 99 wt % adjusted yield. HRMS calcdfor C₄₆H₅₀Cl₂N₄NaO₁₈ [2M+Na]⁺1039.2395 found 1039.2408.

Step 2:(S)-5-((S)-1-amino-2-(benzo[d][1,3]-dioxol-5-yl)ethyl)-3-((S)-2,2-spirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-yl)oxazolidin-2-onebis hydrochloride (41 (HCl)₂6

A 3-necked 1 L RBF was charged with 2 (118 mmol, 1.0 equiv), 3 (32.5 g,124 mmol, 1.05 equiv) and 2-Methyl THF (180 mL). The flask was vacuumdegassed and back-filled with argon (4×). The contents of the flask werewarmed to an internal temperature of 65-70° C. and maintained at thistemperature until judged complete by HPLC analysis. After 12 hours, thereaction mixture was cooled to 0° C. internal temperature and a solutionof KOt-Am (150 mL, 1.7 M in toluene; 250 mmol; 2.1 equiv) was chargeddropwise via addition funnel at such a rate not to exceed 10° C.internal temperature (total addition time=40 minutes; Tmax=10° C.). Thereaction mixture was stirred at 0° for 1 hour and a sample was pulledfor HPLC analysis, until no remaining 4; and r×n was complete. Thereaction was quenched with 20 mL of 10% (wt/wt) aqueous potassiumhydrogen carbonate and stirred for 10 minutes at 10° C. A solution of10% (wt/wt) aqueous potassium carbonate (K₂CO₃; 360 mL) was charged andthe reaction mixture was warmed to 30° C. and stirred until a cleanphase separation was achieved (˜10 minutes). The phases were separatedand aqueous layer was set aside (labeled as 1^(st) aqueous). Theorganics were washed with 10% (wt/wt) aqueous K₂CO₃ again and theaqueous layer was set aside (labeled as 2^(nd) aqueous). The organicswere washed with 240 mL of 25% (wt/wt) aqueous citric acid. The phaseswere separated and the aqueous layer was set aside (labeled as 3^(rd)aqueous). Washed organics with 240 mL of 10% (wt/wt) aqueous K₂CO₃. Thephases were separated and the aqueous layer was set aside (labled as4^(th) aqueous). The organics were concentrated in vacuo and chased with3×300 mL of n-BuOH. A ¹H NMR of the solution revealed that there was nodetectable toluene or 2-MeTHF in the n-BuOH chases.

The n-BuOH solution of 5 was transferred to a clean 1 L RBF and thetotal volume of the reaction was adjusted to 180 mL of n-BuOH and HCl(3N in n-BuOH, 117 mL, 3 equiv) was charged and the reaction was warmedto an internal temperature of 75° C. Reaction was judged complete byHPLC after 30 minutes. The reaction was warmed slightly to 80° C. andstirred at 80° C. for 60 minutes. n-BuOAc (400 mL) was charged slowlyover 1 hour to the crystallization and upon completion of the addition,the mixture was held at 80° C. for 5 hours and cooled over 10 hours toambient temperature and stirred for 30 hours. Analysis of thesupernatant revealed a mother liquor concentration of 1 mg/mL of6-(HCl)₂ and the reaction mixture was filtered. The mother liquors wererecycled to the 1 L RBF and passed back through the wetcake tofacilitate the complete transfer of the solids to the filter. Thewetcake was rinsed with 2×180 mL of 2:1 mixture of n-BuOAc:n-BuOH andthe wetcake was dried on the filter by passing nitrogen through thefilter for 2 hours. The solids were loaded into a vacuum oven and driedfor 24 hours at 80° C. under vacuum with a nitrogen sweep to afford6-(HCl)₂ (100% isolated yield; 100% LCAP 224 nm; 101 wt % assay;Analytical data for 6-(HCl)₂: HRMS calcd for C₅₆H₇₁N₆O₁₀ [2M+H]⁺987.5232 found 987.5218; HRMS calc for C₂₈H₃₆N₃O₅ [M+H]⁺ 494.2655 found494.4595.

Step 3:(2S,3S)-3-amino-4-(benzo[d])[1,3]dioxol-5-yl)-1-((S)-2,2-sipirocyclobutyl-6-neopentyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-4-ylamino)butan-2-ol(30-(HCl)₃)

A 1 L 3-necked RBF was charged with 57 g of 6-(HCl)₂ and 170 mL ofethanol. The flask was vacuum purged and back-filled with argon (3×). A5N aqueous potassium hydroxide solution (190 mL) was added to thereaction mixture. The reaction was warmed to an internal temperature of80° C. and monitored by HPLC. At 18 hours, the reaction mixture wascooled to 25° C. and then a solution of 6N aqueous HCl (120 mL; 6 equiv)was charged to the reaction mixture followed by toluene (340 mL). Asample of the aqueous was pulled for pH (7) and the pH was adjusted with50 mL of 5N KOH to >14. The extraction was warmed to an internaltemperature of 40° C. and was stirred for 1 hour. The phases wereseparated and the aqueous layer was back-extracted with 110 mL oftoluene. The organics were combined and concentrated to ˜1 volume andchased 2×250 mL of IPA. The IPA solution of the reaction mixture waspassed through a medium porosity frit to a tared 1 L 3-necked RBF andthe volume was adjusted to 3 total volumes of IPA. A sample of thissolution was pulled for ¹H NMR analysis which showed no residual toluenepresent in solution.

A solution of HCl in IPA (5M, 60 mL, 3 equiv) was charged to thesolution of the free diaminoalcohol in IPA over 10. The crystallizationmixture was warmed to an internal temperature of 55° C. and 2 volumes oftoluene (110 mL) was charged and held for 30 minutes whereupon thedesired 7-(HCl)₃ salt began to precipitate. The crystallization was heldfor a further 15 minutes at 55° C. whereupon an additional charge oftoluene (385 mL; 6 volumes) was added at such a rate to maintaininternal temperature at 55° C. (˜10 minute addition time). Thecrystallization was maintained at 55-60° C. for 2 hours and then cooledto ambient temperature. The contents of the flask were filtered and themother liquors were recycled to the RBF and then through the filter tofacilitate complete solid transfer. The wetcake was washed with 160 mLof 2:1 toluene:IPA and dried on the filter by passing nitrogen throughthe wetcake for 12 hours. The solids were then loaded into a vacuum ovenand dried under vacuum for 24 hours at 85° C. with a nitrogen purge.Isolated 7-(HCl)₃ as a colorless solid (93% isolated yield; 102 wt %assay, 99.8% LCAP 224 nm; 93 wt % adjusted yield; 17.7 wt % chloride byIC). Analytical data for 7.(HCl)₃: HRMS calc for C₂₇H₃₈N₃O₄ [M+H]⁺468.2862 found 468.4176.

As can be appreciated by the skilled artisan, the above syntheticschemes and representative examples are not intended to comprise acomprehensive list of all means by which the compounds described andclaimed in this application may be synthesized. Further methods will beevident to those of ordinary skill in the art. Additionally, the varioussynthetic steps described above may be performed in an alternatesequence or order to give the desired compounds.

For example, in these procedures, the steps may be preceded, orfollowed, by additional protection/deprotection steps as necessary.Particularly, if one or more functional groups, for example carboxy,hydroxy, amino, or mercapto groups, are or need to be protected inpreparing the compounds of the invention, because they are not intendedto take part in a specific reaction or chemical transformation, variousknown conventional protecting groups may be used. For example,protecting groups typically utilized in the synthesis of natural andsynthetic compounds, including peptides, nucleic acids, derivativesthereof and sugars, having multiple reactive centers, chiral centers andother sites potentially susceptible to the reaction reagents and/orconditions, may be used.

Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the inhibitorcompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 3^(rd) edition, John Wiley andSons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); A. Katritzky and A.Pozharski, Handbook of Heterocyclic Chemistry, 2^(nd) edition (2001); M.Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis,Springer-Verlag, Berlin Heidelberg (1984); J. Seyden-Penne, Reductionsby the Alumino- and Borohydrides in Organic Synthesis, 2^(nd) edition,Wiley-VCH, (1997); and L. Paquette, editor, Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995).

Salts, including pharmaceutically acceptable salts, of a compound of theinvention having a salt-forming group may be prepared in a conventionalmanner or manner known to persons skilled in the art. For example, acidaddition salts of compounds of the invention may be obtained bytreatment with an acid or with a suitable anion exchange reagent. A saltwith two acid molecules (for example a dihalogenide) may also beconverted into a salt with one acid molecule per compound (for example amonohalogenide); this may be done by heating to a melt, or for exampleby heating as a solid under a high vacuum at elevated temperature, forexample from 50° C. to 170° C., one molecule of the acid being expelledper molecule of the compound.

Acid salts can usually be converted to free-base compounds, e.g. bytreating the salt with suitable basic agents, for example with alkalimetal carbonates, alkali metal hydrogen carbonates, or alkali metalhydroxides, typically potassium carbonate or sodium hydroxide. Exemplaryand suitable salts, and their preparation, are described herein in theDefinition section of the application.

All synthetic procedures described herein can be carried out under knownreaction conditions, advantageously under those described herein, eitherin the absence or in the presence (usually) of solvents or diluents. Asappreciated by those of ordinary skill in the art, the solvents shouldbe inert with respect to, and should be able to dissolve, the startingmaterials and other reagents used. Solvents should be able to partiallyor wholly solubilize the reactants in the absence or presence ofcatalysts, condensing agents or neutralizing agents, for example ionexchangers, typically cation exchangers for example in the H⁺ form. Theability of the solvent to allow and/or influence the progress or rate ofthe reaction is generally dependant on the type and properties of thesolvent(s), the reaction conditions including temperature, pressure,atmospheric conditions such as in an inert atmosphere under argon ornitrogen, and concentration, and of the reactants themselves.

Suitable solvents for conducting reactions to synthesize compounds ofthe invention include, without limitation, water; esters, includinglower alkyl-lower alkanoates, e.g., EtOAc; ethers including aliphaticethers, e.g., Et₂O and ethylene glycol dimethylether or cyclic ethers,e.g., THF; liquid aromatic hydrocarbons, including benzene, toluene andxylene; alcohols, including MeOH, EtOH, 1-propanol, IPOH, n- andt-butanol; nitrites including CH₃CN; halogenated hydrocarbons, includingCH₂Cl₂, CHCl₃ and CCl₄; acid amides including DMF; sulfoxides, includingDMSO; bases, including heterocyclic nitrogen bases, e.g. pyridine;carboxylic acids, including lower alkanecarboxylic acids, e.g., AcOH;inorganic acids including HCl, HBr, HF, H₂SO₄ and the like; carboxylicacid anhydrides, including lower alkane acid anhydrides, e.g., aceticanhydride; cyclic, linear, or branched hydrocarbons, includingcyclohexane, hexane, pentane, isopentane and the like, and mixtures ofthese solvents, such as purely organic solvent combinations, orwater-containing solvent combinations e.g., aqueous solutions. Thesesolvents and solvent mixtures may also be used in “working-up” thereaction as well as in processing the reaction and/or isolating thereaction product(s), such as in chromatography.

Purification methods are known in the art and include, for example,crystallization, chromatography (liquid and gas phase, and the like),extraction, distillation, trituration, reverse phase HPLC and the like.Reactions conditions such as temperature, duration, pressure, andatmosphere (inert gas, ambient) are known in the art and may be adjustedas appropriate for the reaction.

The invention further encompasses “intermediate” compounds, includingstructures produced from the synthetic procedures described, whetherisolated or generated in-situ and not isolated, prior to obtaining thefinally desired compound. Structures resulting from carrying out stepsfrom a transient starting material, structures resulting from divergencefrom the described method(s) at any stage, and structures formingstarting materials under the reaction conditions are all “intermediates”included in the invention. Further, structures produced by usingstarting materials in the form of a reactive derivative or salt, orproduced by a compound obtainable by means of the process according tothe invention and structures resulting from processing the compounds ofthe invention in situ are also within the scope of the invention.

The invention also provides new starting materials and/or intermediates,as well as processes for the preparation thereof. In select embodiments,such starting materials are used and reaction conditions so selected asto obtain the desired compound(s). Starting materials of the invention,are either known, commercially available, or can be synthesized inanalogy to or according to methods that are known in the art. Manystarting materials may be prepared according to known processes and, inparticular, can be prepared using processes described in the examples.In synthesizing starting materials, functional groups may be protectedwith suitable protecting groups when necessary. Protecting groups, theirintroduction and removal are described above.

Compounds of the present invention can possess, in general, one or moreasymmetric carbon atoms and are thus capable of existing in the form ofoptical isomers as well as in the form of racemic or non-racemicmixtures thereof. The optical isomers can be obtained by resolution ofthe racemic mixtures according to conventional processes, e.g., byformation of diastereoisomeric salts, by treatment with an opticallyactive acid or base. Examples of appropriate acids are tartaric,diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, andcamphorsulfonic acid and then separation of the mixture ofdiastereoisomers by crystallization followed by liberation of theoptically active bases from these salts. A different process forseparation of optical isomers involves the use of a chiralchromatography column optimally chosen to maximize the separation of theenantiomers. Still another available method involves synthesis ofcovalent diastereoisomeric molecules by reacting compounds of theinvention with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds of theinvention can likewise be obtained by using optically active startingmaterials. These isomers may be in the form of a free acid, a free base,an ester or a salt. All such isomeric forms of such compounds areexpressly included in the present invention.

The compounds of this invention may also be represented in multipletautomeric forms. The compounds may also occur in cis- or trans- or E-or Z-double bond isomeric forms. The invention expressly includes alltautomeric forms of the compounds described herein.

All crystal forms of the compounds described herein are expresslyincluded in the present invention.

Biological Evaluation

The compounds of the invention may be modified by appending appropriatefunctionalities to enhance selective biological properties.Surprisingly, the compounds of the present invention exhibit improvedpharmacokinetics and pharmacodynamics, which relate, directly andindirectly, to the ability of the compound to be effective for itsintended use. For example, the compounds have been surprisingly found topossess improved clearance and efflux properties, which readily lendthemselves to projecting in-vivo PK and PD properties, which in turnassist in projection of therapeutic target coverage for the compoundsand projected efficacious dosages via in-vivo absorption, distribution,metabolism and excretion properties. Increased biological penetrationinto a given biological compartment (e.g., blood, lymphatic system,central nervous system), increase oral availability, increase solubilityto allow administration by injection and alter clearance, metabolismand/or rate of excretion are important factors for discovering whichcompound may be a useful drug and which may not.

Although the pharmacological properties of the compounds of theinvention (Formulas I-IV) vary with structural change, in general,activity possessed by compounds of Formulas I-IV may be demonstratedboth in vitro as well as in vivo. The following exemplifiedpharmacological assays have been carried out with the compoundsaccording to the invention, to assess and characterize the compound'sability to modulate BACE activity and to regulate the cleavage ofamyloid beta precursor protein, thereby reducing or inhibiting theproduction of amyloid beta.

In Vitro Enzymatic BACE FRET (Fluorescence Resonance Energy Transfer)Assay (Enzyme Assay Data in Table 1)

The assay buffer used in this screen is 0.05 M acetate, pH 4.2, 10% DMSOfinal, 100 uM genapol (which is a nonionic detergent, below its CriticalMicelle Concentration). The Beta Secretase enzyme (0.2 nM) ispre-incubated for one hour with inhibitors, typically in about 1 uL ofDMSO according to a serial dilution, are added thereto. The assay iseffectively started by the addition of FRET substrate (50 nM) and thecombination is incubated for one hour. The FRET assay is terminated withby addition of Tris buffer, which raises the pH to neutrality, and thefluorescence is determined. The FRET substrate is a peptide withcommercially available fluorophore and quencher, on opposite sides ofthe BACE cleavage site. Proteolytic cleavage of the FRET substratereleases quenching of fluorescence (excitation 488 nm and emission 425nm).

Of the compounds tested, the in-vitro BACE FRET enzyme data for each ofExamples 52-363 is provided in Table 1. The vast majority of theseexamples exhibited activities with IC₅₀ values of 5 μM or less inin-vitro BACE FRET assay, and a majority of those same Examplesexhibited activities with IC₅₀ values of 100 nM or less in the in-vitroBACE FRET assay

In Vitro BACE Cell-Based Assay:

The cell-based assay measures inhibition or reduction of Aβ40 inconditioned medium of test compound treated cells expressing amyloidprecursor protein.

Cells stably expressing Amyloid Precursor Protein (APP) were plated at adensity of 40K cells/well in 96 well plates (Costar). The cells werecultivated for 24 hours at 37° C. and 5% CO₂ in DMEM supplemented with10% FBS. The test compounds were then added to cells in 10-point doseresponse concentrations with the starting concentration being either 100μM or 10 μM. The compounds were diluted from stock solutions in DMSO andthe final DMSO concentration of the test compounds on cells was 0.1%.After 24 h of incubation with the test compounds the supernatantconditioned media was collected and the Aβ 40 levels were determinedusing a sandwich ELISA. The IC₅₀ of the compound was calculated from thepercent of control or percent inhibition of Aβ 40 as a function of theconcentration of the test compound.

The sandwich ELISA to detect Aβ 40 was performed in 96 well microtiterplates, which were pre-treated with goat anti-rabbit IgG (Pierce). Thecapture and detecting antibody pair that were used to detect Aβ 40 fromcell supernatants were affinity purified pAb40 (Biosource) andbiotinylated 6E10 (Signet Labs Inc.), respectively. The optimalconcentration for the pAb40 antibody was 3 μg/ml in Superblock/TBS(Pierce) that was supplemented with 0.05% Tween 20 (Sigma). Optimalconcentration for the detection antibody 6E10-biotinylated was 0.5 μg/mlin Superblock/TBS (Pierce) that had been supplemented with 2% normalgoat serum and 2% normal mouse serum.

Cellular supernatants were incubated with the capture antibody for 3 hat 4° C., followed by 3 wash steps in TBS-tween (0.05%). The detectingantibody incubation was for 2 h at 4° C., again followed by the washsteps as described previously. The final readout of the ELISA isTime-Resolved Fluorescence (counts per minute) using Delfia reagentsStreptavidin-Europium and Enhancement solutions (Perkin Elmer) and theVictor 2 multilabel counter (Perkin Elmer).

Of the compounds tested, the cell based assay data for each of Examples52-363 is provided in Table 1. The vast majority of those Examplesexhibited activities with IC₅₀ values of 5 μM or less in the cell-basedassay, a majority of those same Examples exhibited activities with IC₅₀values of 1 μM or less in the cell-based assay, and a majority of thosesame Examples exhibited activities with IC₅₀ values of 100 nM or less inthe cell-based assay.

In Vivo Inhibition of Beta-Secretase

Several animal models, including mouse, rat, dog, and monkey, may beused to screen for inhibition of beta-secretase activity in vivofollowing administration of a test compound sample. Animals used in thisinvention can be wild type, transgenic, or gene knockout animals. Forexample, the Tg2576 mouse model, prepared and conducted as described inHsiao et al., 1996, Science 274, 99-102, and other non-transgenic orgene knockout animals are useful to analyze in vivo inhibition ofAmyloid beta peptide (Abeta) production in the presence of inhibitorytest compounds. Generally, 2 to 18 month old Tg2576 mice, gene knockoutmice or non-transgenic animals are administered test compoundsformulated in vehicles, such as cyclodextran, phosphate buffers,hydroxypropyl methylcellulose or other suitable vehicles. One totwenty-four hours following the administration of compound, animals aresacrificed, and brains as well as cerebrospinal fluid (CSF) and plasmaare removed for analysis of A-beta levels and drug or test compoundconcentrations (Dovey et al., 2001, Journal of Neurochemistry,76,173-181) Beginning at time 0, animals are administered by oralgavage, or other means of delivery such as intravenous injection, aninhibitory test compound of up to 100 mg/kg in a standard, conventionalformulation, such as 2% hydroxypropyl methylcellulose, 1% Tween80. Aseparate group of animals receive 2% hydroxypropyl methylcellulose, 1%Tween80 alone, containing no test compound, and serve as avehicle-control group. At the end of the test period, animals aresacrificed and brain tissues, plasma or cerebrospinal fluid arecollected. Brains are either homogenized in 10 volumes (w/v) of 0.2%diethylamine (DEA) in 50 mM NaCl (Best et al., 2005, Journal ofPharmacology and Experimental Therapeutics, 313, 902-908), or in 10volumes of 0.5% TritonX-100 in Tris-buffered saline (pH at about 7.6).Homogenates are centrifuged at 355,000 g, 4° C. for 30 minutes. CSF orbrain supernatants are then analyzed for the presence of Abeta peptideby specific sandwich ELISA assays based on ECL(Electrochemiluminescence) technology. For example, rat Abeta40 ismeasured using biotinylated-4G8 (Signet) as a capture antibody and Fab40(an in-house antibody specific to the C-terminal of Abeta40) as adetection antibody. For example, 4 hours after administration of 30mg/kg oral dose of the test compound in 2% hydroxypropylmethylcellulose, 1% Tween80 (pH2.2) to 200 g male Sprague Dawley rats,Abeta peptide levels are measured for reduction by X % and Y % incerebrospinal fluid and brain, respectively, when compared to the levelsmeasured in the vehicle-treated or control mice.

Actual vehicles used: Oral: 2% HPMC, 1% Tween80, pH 2.2

-   -   IV: 5% EtOH, 45% Propylene glycol in 5% Dextrose

The compounds of the invention can be shown to reduce the formationand/or deposition of Abeta peptide in the brain or in the cerebrospinalfluid of a mouse or rat. For example, many of the Examples testedexhibited activities with percent (%) reduction values of Abeta peptideof up to 78% in the brain or in the cerebrospinal fluid of a rat, whenorally administered to the rat at a 30 mg/kg dose and measured after 4hours. More specifically, Example numbers 484, 488, 523, 578, 600, 643,644, 650, 661, 677, 690, 695, 699, 736-738, 756-757, 761, 772-773,776-777, 782, 790, 816-817, 826, 828-830, 834, 835, 840, 844, 847,849-850, 855-856, 861, 870, 873, 875, 878-879, 893-894, 896-898 and900-903, exhibited a percent reduction of abeta peptide in the range offrom 5% to 80% in the brain of the rat. Example numbers 644, 695, 699,736-738, 743, 756-757, 761, 772-773, 776-777, 790, 817, 829, 834, 844,849-850, 855-856, 861, 870, 873, 896-898 and 900-903, exhibited apercent reduction of abeta peptide in the range of greater than or equalto 30% in the brain of the rat. Example numbers 478, 483, 484, 488, 504,506, 516, 521, 523, 528, 529, 531-533, 535, 541, 542, 575, 578, 583-587,596-597, 600, 619-621, 628, 630-633, 636, 638, 640-641, 643-644, 650,652, 661, 671, 673, 677, 682-684, 687, 690, 695, 698, 699, 704-706, 710,712, 714-716, 722, 724, 747, 730, 731, 736-738, 743, 756-757, 761, 764,772-773, 775, 776-777, 782, 790, 816-817, 826, 828-830, 831, 834, 836,837, 840, 844-850, 855-856, 859-861, 868-871, 873-875, 877-879, 883,885, 893-894, 900 and 902, exhibited a percent reduction of abetapeptide in the range of from 10% to 80% in the cerebrospinal fluid ofthe rat, when orally administered at 30 mg/kg dose and measured after 4hours. Example numbers 578, 644, 650, 661, 690, 695, 699, 722, 724,736-738, 757, 761, 772-773, 776-777, 790, 817, 834, 840, 844, 847,849-850, 855-856, 861, 870 and 873, exhibited a percent reduction ofabeta peptide in the range of greater than or equal to 50% in thecerebrospinal fluid of the rat.

CYP Inhibition Assay:

The CYP enzymes in the body are known to function in the metabolicpathway of a given compound. More specifically, CYP enzymes areresponsible for metabolic breakdown of compounds. Thus, modulating theactivity of one or more of the various CYP enzymes may influencepotential metabolism of an administered compound. Particularly, if thecompounds of the present invention were to inhibit the CYP enzyme, theymay, thereby, reduce the rate of potential in-vivo metabolism of thecompound, thus possibly prolonging the bioavailability of that compound.The compounds of the invention were run in the following CYP assays todetermine their potential to inhibit specific CYP enzymes.

CYP3A

Pooled human liver microsomes (0.1 mg/mL) are incubated at about 37° C.in a phosphate buffer (pH 7.4) with the selective 3A substrate midazolamat a concentration of about 2.5 μM in the presence and absence of a testcompound (at about 3 μM conc.). The reaction is started with theaddition of NADPH (1 mM final concentration). Incubations are stoppedafter 10 minutes with the addition of organic solvent and1-hydroxymidazolam metabolite formation is measured by an HPLC MSdetection method. The ability of the test compound to inhibit theactivity of CYP3A is determined (either % inhibition or an IC₅₀ can bemeasured in uM) by the ratio of the amount of metabolite in the presenceof the test compound to the amount of metabolite in the absence of testcompound. Data for various compounds of the invention in this assay isprovided in Table 3.

CYP2D6

Pooled human liver microsomes (0.25 mg/mL) are incubated at about 37° C.in a phosphate buffer (pH 7.4) with the selective 2D6 substratebufuralol at a concentration of about 5 μM in the presence and absenceof a test compound (at about 3 μM conc.). The reaction is started withthe addition of NADPH (1 mM final concentration). Incubations arestopped after 10 minutes with the addition of organic solvent and1-hydroxybufuralol metabolite formation is measured by an HPLC MSdetection method. The ability of the test compound to inhibit theactivity of CYP2D6 is determined (either % inhibition or an IC₅₀ can bemeasured in uM) by the ratio of the amount of metabolite in the presenceof test compound to the amount of metabolite in the absence of testcompound. Data for various compounds of the invention in this assay isprovided in Table 3.

Microsomal Stability Assay

The purpose of this assay is to determine to what extent a compound maysurvive metabolic forces and to help ascertain the degree, time andextent of metabolism of a given compound. Such data is useful forprojecting a given compound's ability to remain the plasma andpotentially reach a desired target.

Assay: Pooled human or rat liver microsomes (0.25 mg/mL) are incubatedat about 37° C. in a phosphate buffer (pH 7.4) with a test compound (ata concentration of about 1 μM). The reaction is started with theaddition of NADPH (1 mM final concentration). Incubations are stoppedafter 0 or 30 minutes with the addition of organic solvent. Quenchedsamples are analyzed for unchanged test compound by reverse phase HPLCwith tandem mass spectrometric detection. % Turnover is determined bythe ratio of the amount (peak area) of unchanged test compound remainingin incubated samples to the amount of unchanged test compound innon-incubated samples (0 minutes). Intrinsic clearance is estimatedassuming first order elimination of compound from the incubation overthe 30 minute incubation. Data for various compounds of the invention inthis assay (human and rat) is provided in Table 3.

Indications

Accordingly, compounds of the invention are useful for, but not limitedto, the prevention or treatment of beta-secretase related diseases,including Alzheimer's disease.

The compounds of the invention have the ability to modulate the activityof beta secretase enzyme, thereby regulating the production of amyloidbeta (Abeta peptide) and reducing the formation and deposition of Abetapeptide and/or plaque on the brain. In one embodiment of the invention,there is provided a method of treating a disorder related to abeta-secretase enzyme in a subject, the method comprising administeringto the subject an effective dosage amount of a compound of FormulasI-IV. In another embodiment, there is provided a method of reducingproduction of amyloid beta, and of reducing plaque formation. In anotherembodiment, there is provided a method for the treatment, prevention oramelioration of a disease or disorder characterized by the elevatedbeta-amyloid deposits or beta-amyloid levels in a subject, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound according to any of Formulas I, II, II-A, II-B,II-C, II-D, III-A, III-B, III-C and III-D. In yet another embodiment,the invention provides a method of treating Alzheimer's disease,cognitive impairment including mild, moderate and/or severe, Down'sSyndrome, cognitive decline, senile dementia, cerebral amyloidangiopathy or a neurodegenerative disorder.

Accordingly, the compounds of the invention would be useful in therapyas CNS agents in treating neurological disorders and related conditions.

Besides being useful for human treatment, these compounds are useful forveterinary treatment of companion animals, exotic animals and farmanimals, including mammals, rodents, and the like. For example, animalsincluding horses, dogs, and cats may be treated with compounds providedby the invention.

Formulations and Method of Use

Treatment of diseases and disorders herein is intended to also includetherapeutic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman) which may be in need of preventative treatment, such as, forexample, for pain, inflammation and the like. Treatment also encompassesprophylactic administration of a compound of the invention, or apharmaceutical salt thereof, or a pharmaceutical composition of eitherto a subject (i.e., an animal, preferably a mammal, most preferably ahuman). Generally, the subject is initially diagnosed by a licensedphysician and/or authorized medical practitioner, and a regimen forprophylactic and/or therapeutic treatment via administration of thecompound(s) or compositions of the invention is suggested, recommendedor prescribed.

The amount of compound(s) which is/are administered and the dosageregimen for treating neurological disorders and beta-secretase mediateddiseases with the compounds and/or compositions of this inventiondepends on a variety of factors, including the age, weight, sex andmedical condition of the subject, the type of disease, the severity ofthe disease, the route and frequency of administration, and theparticular compound employed. Thus, the dosage regimen may vary widely,but can be determined routinely using standard methods. A daily dose ofabout 0.01 to 500 mg/kg, advantageously between about 0.01 and about 50mg/kg, more advantageously about 0.01 and about 30 mg/kg, and even moreadvantageously between about 0.1 and about 10 mg/kg body weight may beappropriate, and should be useful for all methods of use disclosedherein. The daily dose can be administered in one to four doses per day.

While it may be possible to administer a compound of the inventionalone, in the methods described, the compound administered normally willbe present as an active ingredient in a pharmaceutical composition.Thus, in another embodiment of the invention, there is provided apharmaceutical composition comprising a compound of this invention incombination with a pharmaceutically acceptable excipient, which includesdiluents, carriers, adjuvants and the like (collectively referred toherein as “excipient” materials) as described herein, and, if desired,other active ingredients. A pharmaceutical composition of the inventionmay comprise an effective amount of a compound of the invention or aneffective dosage amount of a compound of the invention. An effectivedosage amount of a compound of the invention includes an amount lessthan, equal to or greater than an effective amount of the compound. Forexample, a pharmaceutical composition in which two or more unit dosages,such as in tablets, capsules and the like, are required to administer aneffective amount of the compound, or alternatively, a multi-dosepharmaceutical composition, such as powders, liquids and the like, inwhich an effective amount of the compound is administered byadministering a portion of the composition.

The compound(s) of the present invention may be administered by anysuitable route, preferably in the form of a pharmaceutical compositionadapted to such a route, and in a dose effective for the treatmentintended. The compounds and compositions of the present invention may,for example, be administered orally, mucosally, topically, rectally,pulmonarily such as by inhalation spray, or parentally includingintravascularly, intravenously, intraperitoneally, subcutaneously,intramuscularly intrasternally and infusion techniques, in dosage unitformulations containing conventional pharmaceutically acceptablecarriers, adjuvants, and vehicles.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are tablets or capsules. For example, these maycontain an amount of active ingredient from about 1 to 2000 mg,advantageously from about 1 to 500 mg, and typically from about 5 to 150mg. A suitable daily dose for a human or other mammal may vary widelydepending on the condition of the patient and other factors, but, onceagain, can be determined using routine methods and practices.

For therapeutic purposes, the active compounds of this invention areordinarily combined with one or more adjuvants or other “excipients”appropriate to the indicated route of administration. If orallyadministered on a per dose basis, the compounds may be admixed withlactose, sucrose, starch powder, cellulose esters of alkanoic acids,cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, to form the final formulation. For example,the active compound(s) and excipient(s) may be tableted or encapsulatedby known and accepted methods for convenient administration. Examples ofsuitable formulations include, without limitation, pills, tablets, softand hard-shell gel capsules, troches, orally-dissolvable forms anddelayed or controlled-release formulations thereof. Particularly,capsule or tablet formulations may contain one or morecontrolled-release agents, such as hydroxypropylmethyl cellulose, as adispersion with the active compound(s).

Formulations for parenteral administration may be in the form of aqueousor non-aqueous isotonic sterile injection solutions or suspensions.These solutions and suspensions may be prepared from sterile powders orgranules using one or more of the carriers or diluents mentioned for usein the formulations for oral administration or by using other suitabledispersing or wetting agents and suspending agents. The compounds may bedissolved in water, polyethylene glycol, propylene glycol, ethanol, cornoil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodiumchloride, tragacanth gum, and/or various buffers. Other adjuvants andmodes of administration are well and widely known in the pharmaceuticalart. The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water,or with cyclodextrin (ie. Captisol), cosolvent solubilization (ie.propylene glycol) or micellar solubilization (ie. Tween 80).

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution, and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employed,including synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The active ingredient may also be administered by injection as acomposition with suitable carriers including saline, dextrose, or water.The daily parenteral dosage regimen will be from about 0.1 to about 30mg/kg of total body weight, and preferably from about 0.1 to about 10mg/kg.

For pulmonary administration, the pharmaceutical composition may beadministered in the form of an aerosol or with an inhaler including drypowder aerosol.

The pharmaceutical compositions may be subjected to conventionalpharmaceutical operations such as sterilization and/or may containconventional adjuvants, such as preservatives, stabilizers, wettingagents, emulsifiers, buffers etc. Tablets and pills can additionally beprepared with enteric coatings. Such compositions may also compriseadjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

Accordingly, in yet another embodiment of the present invention, thereis provided a method of manufacturing a medicament, the methodcomprising combining an amount of a compound according to Formulas I-IVwith a pharmaceutically acceptable carrier to manufacture themedicament.

In yet another embodiment, the invention provides a method ofmanufacturing a medicament for the treatment of Alzheimer's disease, themethod comprising combining an amount of a compound according toFormulas I-IV with a pharmaceutically acceptable carrier to manufacturethe medicament.

Combinations

While the compounds of the invention can be dosed or administered as thesole active pharmaceutical agent, they can also be used in combinationwith one or more compounds of the invention or in conjunction with otheragents. When administered as a combination, the therapeutic agents canbe formulated as separate compositions that are administeredsimultaneously or sequentially at different times, or the therapeuticagents can be given as a single composition.

The phrase “co-therapy” (or “combination-therapy”), in defining use of acompound of the present invention and another pharmaceutical agent, isintended to embrace administration of each agent in a sequential mannerin a regimen that will provide beneficial effects of the drugcombination, and is intended as well to embrace co-administration ofthese agents in a substantially simultaneous manner, such as in a singlecapsule having a fixed ratio of these active agents or in multiple,separate capsules for each agent.

Specifically, the administration of compounds of the present inventionmay be in conjunction with additional therapies known to those skilledin the art in the prevention or treatment of beta-secretase,gamma-secretase and/or other reagents known in influence the formationand/or deposition of amyloid beta, otherwise responsible for theformation of plaque on the brain.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the accepted dosage ranges. Compoundsof Formulas I and II may also be administered sequentially with knownanti-inflammatory agents when a combination formulation isinappropriate. The invention is not limited in the sequence ofadministration; compounds of the invention may be administered eitherprior to, simultaneous with or after administration of the knownanti-inflammatory agent.

The foregoing description is merely illustrative of the invention and isnot intended to limit the invention to the disclosed compounds,compositions and methods. Variations and changes, which are obvious toone skilled in the art, are intended to be within the scope and natureof the invention, as defined in the appended claims. From the foregoingdescription, one skilled in the art can easily ascertain the essentialcharacteristics of this invention, and without departing from the spiritand scope thereof, can make various changes and modifications of theinvention to adapt it to various usages and conditions. All patents andother publications recited herein are hereby incorporated by referencein their entireties.

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein A¹ is CH; A² isCR⁶; each of A³ and A⁴, independently, is N, CH or CR⁶, provided that nomore than one of A³ and A⁴ is N; R^(1a) is H, halo, haloalkyl,C₁₋₆-alkyl, —O—C₁₋₆-alkyl, or OH, wherein the C₁₋₆-alkyl and C₁₋₆-alkylportion of —O—C₁₋₆-alkyl, are optionally substituted independently with1-5 substituents of R⁷; R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—C₁₋₆-alkyl, or OH, wherein the C₁₋₆-alkyl and C₁₋₆-alkyl portion of—O—C₁₋₆-alkyl, are optionally substituted independently with 1-5substituents of R⁷; R^(1c) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, or OH; W is —C(═O)—, each R², independently, is halo,haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, CN, OH, NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, wherein the C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl and theC₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted with 1-5 substituents of R⁷;alternatively, two adjacent R² groups taken together with the carbonatoms to which they are attached form a dioxolyl ring optionallysubstituted by 1 or 2 halo; R^(2a) is H or F; R³ is CN, C₂₋₃alkynyl, apartially or fully unsaturated 5-or 6-membered monocyclic ring formed ofcarbon atoms wherein said ring optionally including 1-3 heteroatomsselected from O, N, or S and optionally substituted with 1-5substituents of R⁷, or R³ is F or absent when two adjacent R² groupstaken together with the carbon atoms to which they are attached form adioxolyl ring; R⁴ is H, halo or C₁₋₆-alkyl; R⁵ is H, halo, haloalkyl,oxo, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆alkyl,—N-di-C₁₋₆-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyl and theC₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted independently with 1-5substituents of R⁷; X is CH₂, CHR⁶, —C(═O) or O, Z is a 4-memberedspirocyclic ring formed of carbon atoms optionally substitutedindependently with 1-5 substituents of R⁷; each R⁶, independently, ishalo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl,—NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, wherein theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷; or R⁶ is a fully saturated orpartially or fully unsaturated 5-or 6-membered monocyclic or bicyclicring formed of carbon atoms, said ring optionally including 1-4heteroatoms selected from O, N, or S and optionally substituted with oneor more substituents of R⁷ each R⁷, independently, is H, halo,haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl,C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-,C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fullysaturated or partially or fully unsaturated 3-8 membered monocyclic or a6-12 membered bicyclic, said ring system formed of carbon atomsoptionally including 1-3 heteroatoms if monocyclic or 1-6 heteroatoms ifbicyclic, said heteroatoms selected from O, N, or S, wherein each of theC₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl; and m is 0, 1, 2 or 3, provided the compound is notN-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((2S,3R)-4-((S)-6-ethyl-2,2′-spirocyclobutylchroman-4-ylamino)-3-hydroxy-1-(4-phenyl-phenyl)-butan-2-yl)acetamide;(3S)—N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-1-cyclobutyl-5-oxo-3-pyrrolidinecarboxamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)propanamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)-2-(cyclopropylmethyl)oxy)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-ethyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;N′-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4)-ylamino)-2-hydroxypropyl)-N,N-dimethylbutanediamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-(methyloxy)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2-(methyloxy)acetamide;N-((1S,2R)-1-((3-cyano-5-fluorophenyl)methyl)-3-(((4S)-6-ethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro-2,2-spirocyclobutyl[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)acetamide;2-(((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4S)-6-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)amino)-2-oxoethyldimethylcarbamate;N-((1S,2R)-3-(((4S)-8-bromo-6-chloro-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1((3-cyanophenyl)methyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4S)-6-chloro-8-(4-morpholinyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((5′S)-3′-methyl-5′,8′-dihydro-6′H-spiro[cyclobutane-1,7′-quinolin]-5′-yl)amino)propyl)acetamide;N-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(trifluoromethyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide;N-((1˜-((1S,2R)-3-(((4S)-6-bromo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-1-((3-cyanophenyl)methyl)-2-hydroxypropyl)—N˜2˜,N˜2˜-dimethylglycinamide;Methyl(4S)-4-(((2R,3S)-4-(3-cyanophenyl)-3-((N,N-dimethylglycyl)amino)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;Methyl(4S)-4-(((2R,3S)-3-(acetylamino)-4-(3-cyanophenyl)-2-hydroxybutyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;Methyl(4S)-4-(((2R,3S)-4-(3-cyanophenyl)-2-hydroxy-3-(((methyloxy)acetyl)amino)butyl)amino)-3,4-dihydrospiro[chromene-2,1′-cyclobutane]-6-carboxylate;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)acetamide;andN-((1S,2R)-1-((3-cyanophenyl)methyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)acetamide.2. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(1a) is C₁₋₆-alkyl, or —O—C₁₋₆-alkyl-, R^(1b) is H,halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, or OH; and R^(1c) is H. 3.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is C₂₋₃alkynyl or a ring selected from phenyl, pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl, furyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl,oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl,pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, pyrazolinyl,morpholinyl, piperidinyl, piperazinyl and pyranyl, said ring optionallysubstituted with 1-5 substituents of R⁷.
 4. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein A¹ is CH; A² is CR⁶;each of A³ and A⁴, independently, CH, CR⁶ or N, provided no more thanone of A³ and A⁴ is N; R^(1a) is C₁₋₆-alkyl, optionally substituted with1-3 substituents of R⁷; R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, or OH; R^(1c) is H; W is —C(═O)—; each R², independently,is halo, haloalkyl, C₁₋₄-alkyl, —O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl,—NH—C₁₋₄-alkyl, —N-di-C₁₋₄-alkyl, CN, OH, NH₂, C₂₋₄-alkenyl,C₂₋₄-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl, wherein theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷; alternatively, two adjacent R²groups taken together with the carbon atoms to which they are attachedform a dioxolyl ring optionally substituted by 1 or 2 halo; R^(2a) is H;R³ is a ring selected from phenyl, pyridyl, pyrimidyl, pyridazinyl,pyrazinyl, triazinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolidinyl, oxazolinyl,isoxazolinyl, thiazolinyl, pyrazolinyl, morpholinyl, piperidinyl,piperazinyl and pyranyl, said ring optionally substituted with 1-5substituents of R⁷, or R³ is absent when two adjacent R² groups takentogether with the carbon atoms to which they are attached form adioxolyl ring; R⁴ is H or C₁₋₄-alkyl; R⁵ is H, halo, haloalkyl,C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, CN, OH or NH₂; X is CH², CHR⁶, C(═O) or O; Z is acyclobutyl ring optionally substituted independently with 1-5substituents of R⁷; and each R⁶, independently, is halo, haloalkyl,C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl or a ring selected from phenyl,pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, thiophenyl,furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl,oxadiazolyl, pyrrolidinyl, oxazolinyl, isoxazolinyl, thiazolinyl,pyrazolinyl, morpholinyl, piperidinyl, piperazinyl and pyranyl, whereinthe C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl, ring and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R7.
 5. The compound of claim 1, ora pharmaceutically acceptable salt thereof, having a general FormulaII-A:

wherein each of A³ and A⁴, independently, CH, CR⁶ or N, provided no morethan one of A³ and A⁴ is N; R^(1a) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, or OH, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portionof —O—C₁₋₆-alkyl, are optionally substituted independently with 1-5substituents of R⁷; R^(1b) is H, halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, or OH, wherein the C₁₋₆-alkyl and the C₁₋₆-alkyl portionof —O—C₁₋₆-alkyl, are optionally substituted independently with 1-5substituents of R⁷; R^(1c) is H, F, Cl, methyl, ethyl, methoxyl,ethyoxyl, or OH; each R², independently, is halo, haloalkyl, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH,NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R7; alternatively, two adjacent R²groups taken together with the carbon atoms to which they are attachedform a dioxolyl ring optionally substituted by 1 or 2 halo; R^(2a) is Hor F; R³ is CN, C₂₋₃alkynyl or a ring selected from imidazolyl,thiazolyl, pyridyl, pyazolyl, furyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, thiophenyl, pyrrolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl or oxadiazolyl, said ringoptionally substituted with 1-3 substituents of R⁷, or R³ is F or absentwhen two adjacent R² groups taken together with the carbon atoms towhich they are attached form a dioxolyl ring; R⁴ is H, halo orC₁₋₄-alkyl; R⁵ is H, halo, haloalkyl, C₁₋₄-alkyl, —O—C₁₋₄-alkyl,—S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, CN, OH or NH₂, wherein the C₁₋₆-alkyl andthe C₁₋₄-alkyl portion of —O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl and —N—C₁₋₄-alkylare optionally substituted independently with 1-3 substituents of R⁷;each R⁶, independently, is halo, haloalkyl, C₁₋₆-alkyl, —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl or C₄ ₋₈-cycloalkenyl,wherein the C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,C₄₋₈-cycloalkenyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl,—S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and —N-di-C₁₋₆-alkyl are optionallysubstituted with 1-5 substituents of R⁷; each R⁷, independently, is H,halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl, oxo, C₁₋₁₀-alkyl,C₁₋₁₀-alkenyl, C₂₋₁₀-alkenyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxylor a fully saturated or partially or fully unsaturated 3-8 memberedmonocyclic or a 6-12 membered bicyclic, said ring system formed ofcarbon atoms optionally including 1-3 heteroatoms if monocyclic or 1-6heteroatoms if bicyclic, said heteroatoms selected from O, N, or S,wherein each of the C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃-₁₀⁻cycloalkyl, C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl and ring of said ring system isoptionally substituted independently with 1-5 substituents of halo,haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl, methoxyl, ethyl, ethoxyl,propyl, propoxyl, isopropyl, isopropoxyl, cyclopropyl,cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl, tert-butoxyl, isobutyl,sec-butyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl,cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-thioalkoxyl,benzyl or phenyl; m is 0, 1, 2 or 3; n is 0, 1 or 2; and p is 0, 1 or 2.6. The compound of claim 5, or a pharmaceutically acceptable saltthereof, wherein R^(1a) is C₁₋₆-alkyl, —O—C₁₋₆-alkyl, wherein theC₁₋₆-alkyl and the C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, is optionallysubstituted independently with 1-5 substituents of R⁷; R^(1b) is H, F,Cl, Br, CF₃, C₂F₅, C₁₋₆-alkyl, —O—C₁₋₆-alkyl, wherein the C₁₋₆-alkyl andthe C₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, is optionally substitutedindependently with 1-3 substituents of R⁷; R^(1c) is H, F, Cl, methyl orethyl; each R², independently, is F, Cl, Br, CF₃, C₂F₅, C₁₋₆-alkyl,—O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl, —N-di-C₁₋₆-alkyl, CN, OH,NH₂, C₂₋₆-alkenyl, C₂₋₆-alkynyl or C₃₋₈-cycloalkyl, wherein theC₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-eyeloalkyl and theC₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted with 1-3 substituents of R⁷;R³ is C₂₋₃alkynyl or a ring selected from 1H-imidazol-1-yl,1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, 1,3-thiazol-5-yl,1,3-thiazol-4-yl, 1,3-thiazol-2-yl, 4-pyridyl, 3-pyridyl, 2-pyridyl,pyrimidyl, pyridazinyl, pyrazinyl, pyrazolyl, 1,3-oxazol-2-yl,1,3-oxazol-4-yl, 1,3-oxazol-5-yl, isoxazolyl, isothiazolyl, thiadiazolyland oxadiazolyl, said ring optionally substituted with 1-3 substituentsof R⁷; R⁴ is H, F or methyl; R⁵ is H, halo, haloalkyl, C₁₋₄-alkyl,—O—C₁₋₄-alkyl, —S—C₁₋₄-alkyl, —NH—C₁₋₄-alkyl, CN, OH or NH₂, wherein theC₁₋₆-alkyl and the C₁₋₄-alkyl portion of —O—C₁₋₄-alkyl, —S—C₁₋₄-alkyland —N—C₁₋₄-alkyl are optionally substituted independently with 1-3substituents of R⁷; each R⁶, independently, is halo, haloalkyl,C₁₋₆-alkyl, —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl,—N-di-C₁₋₆-alkyl, CN, OR⁷, NHR⁷, C₂₋₆-alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl or C₄ ₋₈-cycloalkenyl, wherein the C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl and theC₁₋₆-alkyl portion of —O—C₁₋₆-alkyl, —S—C₁₋₆-alkyl, —NH—C₁₋₆-alkyl and—N-di-C₁₋₆-alkyl are optionally substituted with 1-5 substituents of R⁷;each R⁷, independently, is H, halo, haloalkyl, CN, OH, NO₂, NH₂, acetyl,oxo, C₁₋₁₀-alkyl, C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl,C₄₋₁₀-cycloalkenyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyl or a fully saturated or partially orfully unsaturated 3-8 membered monocyclic or a 6-12 membered bicyclic,said ring system formed of carbon atoms optionally including 1-3heteroatoms if monocyclic or 1-6 heteroatoms if bicyclic, saidheteroatoms selected from O, N, or S, wherein each of the C₁₋₁₀-alkyl,C₂₋₁₀-alkenyl, C₂₋₁₀-alkynyl, C₃₋₁₀-cycloalkyl, C₄₋₁₀-cycloalkenyl,C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-, C₁₋₁₀-alkoxyl, C₁₋₁₀-thioalkoxyland ring of said ring system is optionally substituted independentlywith 1-5 substituents of halo, haloalkyl, CN, NO₂, NH₂, OH, oxo, methyl,methoxyl, ethyl, ethoxyl, propyl, propoxyl, isopropyl, isopropoxyl,cyclopropyl, cyclopropylmethoxyl, butyl, butoxyl, isobutoxyl,tert-butoxyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl,cyclopentyl, hexyl, cyclohexyl, C₁₋₁₀-alkylamino-, C₁₋₁₀-dialkylamino-,C₁₋₁₀-thioalkoxyl, benzyl or phenyl; m is 0, 1 or 2; n is 0 or 1; and pis 0, 1 or
 2. 7. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, selected from(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)tetrahydro-2-furancarboxamide;(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-fluoropropanamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-oxetanecarboxamide;(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-oxetanecarboxamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2,2-dimethoxyacetamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1H-imidazol-1-yl)benzyl)propyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(4-pyridinyl)benzyl)propyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(4-pyridinyl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-8′-chloro-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-5-yl)benzyl)propyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-4-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-5-yl)benzyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1H-imidazol-1-yl)benzyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-4-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-5-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1H-imidazol-1-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-4-yl)benzyl)propyl)-2-methoxyacetamide;N-((1R,2S)-3-(((4S)-6-(2,2-dimethylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)acetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-(methylamino)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;N-((1S,2R)-3-(((1s,3R,4′S)-6′-(2,2-dimethylpropyl)-3-methyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((1s,3S,4′S)-6′-(2,2-dimethylpropyl)-3-hydroxy-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)propanamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1-methyl-1H-imidazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2,2-dimethoxyacetamide;N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(5-methyl-1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-((6′-(2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-3-((6′-(2,2-difluoropropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide;(2R)—N-((1S,2R)-1-(4-fluoro-3-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxypropanamide;N-((1S,2R)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxy-3-(((4S)-6-(2-methylpropyl)-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl)amino)propyl)-2-methoxyacetamide;N-((1S,2R)-1-(1,3-benzodioxol-5-ylmethyl)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxypropyl)-2-ethoxyacetamide;N-((1S,2R)-1-(3-ethynyl-4-fluorobenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxyacetamide;(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;(2S)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro-2-furancarboxamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)tetrahydro-2-furancarboxamide;N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;N-((1S,2R)-3-(((3S,4′S)-6′-(2,2-dimethylpropyl)-3 ′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;N-((1S,2R)-3-(((3S,4′R)-6′-(2,2-dimethylpropyl)-3′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2-fluoro-2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(2-pyridinyl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((3S,4′S)-6′-(2,2-dimethylpropyl)-3′,4,4′,5-tetrahydrospiro[furan-3,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-ethoxyacetamide;N-((1S,2R)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2,2-dimethoxyacetamide;(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)-2-methoxypropanamide;(2R)—N-((1S,2R)-1-(3-ethynylbenzyl)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)propyl)-2-methoxypropanamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynyl-5-fluorobenzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-ethynylbenzyl)-2-hydroxypropyl)-2-ethoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-ethoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxyacetamide;N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2,2-dimethoxyacetamide;N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-oxazol-2-yl)benzyl)propyl)-2-methoxyacetamide;(2R)—N-((1S,2R)-2-hydroxy-3-(((4′S)-6′-(2-methylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide;andN-((1S,2R)-3-(((4′S)-6′-((1R)-2,2-dimethylcyclopropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-ethoxyacetamide.8. A pharmaceutical composition comprising a compound according to claim1 and a pharmaceutically acceptable excipient.
 9. A pharmaceuticalcomposition comprising a compound according to claim 5 and apharmaceutically acceptable excipient.
 10. A pharmaceutical compositioncomprising a compound according to claim 7 and a pharmaceuticallyacceptable excipient.
 11. A process for preparing a compound of claim 1,the process comprising the step of reacting a compound 20,

wherein R², R³, R⁴, R⁵, R⁶, A¹, A², A³, A⁴, X, Z, m and n are as definedin claim 1, with a compound having the structure,

wherein R^(1a), R^(1b) and R^(1c) are as defined in claim 1 and LG is aleaving group selected from a halogen and an HOBt ester, to prepare thecompound of claim
 1. 12. The compound of claim 7, or a pharmaceuticallyacceptable salt thereof, that is(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxypropanamide.13. A pharmaceutical composition comprising a compound according toclaim 12 and a pharmaceutically acceptable excipient.
 14. The compoundof claim 7, or a pharmaceutically acceptable salt thereof, that is(2R)—N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-1-(3-fluoro-5-(1,3-thiazol-2-yl)benzyl)-2-hydroxypropyl)-2-methoxypropanamide.15. A pharmaceutical composition comprising a compound according toclaim 14 and a pharmaceutically acceptable excipient.
 16. The compoundof claim 7, or a pharmaceutically acceptable salt thereof, that isN-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-b]pyridin]-4′-yl)amino)-2-hydroxy-1-(3-(1,3-thiazol-2-yl)benzyl)propyl)-2-methoxyacetamide.17. A pharmaceutical composition comprising a compound according toclaim 16 and a pharmaceutically acceptable excipient.